KR20070050076A - Amido compounds and their use as pharmaceuticals - Google Patents

Abstract

The present invention relates to inhibitors of 11-β hydroxyl steroid dehydrogenase type 1, antagonists of mineralocorticoid receptors (MR) and compositions thereof. The compounds of the present invention may be useful in the treatment of various diseases associated with 11-β hydroxyl steroid dehydrogenase type 1 and / or diseases associated with aldosterone excess.

Inhibitor of 11-β hydroxyl steroid dehydrogenase type 1, antagonist of mineralocorticoid receptor (MR)

Description

Amido compounds and their use as pharmaceuticals}

The present invention relates to modulators of 11-β hydroxyl steroid dehydrogenase type 1 (11βHSD1) and / or mineralocorticoid receptors (MR), compositions thereof and methods of using the same.

Glucocorticoids are steroid hormones that regulate fat metabolism, function and distribution. In vertebrates, glucocorticoids have sufficient and diverse physiological effects on growth, neurobiology, inflammation, blood pressure, metabolism and cell death. The main glycocorticoid produced endogenously in humans is cortisol. Cortisol is synthesized in the multiple layers of the adrenal cortex under the control of short-term neuroendocrine feedback circuits called the hypothalamic-pituitary-adrenal axis (HPA). Cortisol production in the adrenal glands is under the control of corticosteroids (ACTH), a factor produced and secreted by the anterior pituitary gland. The production of ACTH in the anterior pituitary gland is highly regulated and promoted by the corticotropin-releasing hormone (CRH) produced by the hypothalamus nucleus. The HPA axis maintains circulating cortisol concentrations within a limited range, maximally during daytime or stress, and is due to the cortisol's ability to inhibit ACTH production in the anterior pituitary and CRH in the hypothalamus. By reducing quickly.

Aldosterone is another hormone produced by the adrenal cortex, where aldosterone regulates sodium and potassium homeostasis. Fifty years ago, in the description of primary aldosteroneism, the effect of excessive aldosterone on human disease was reported [Conn, (1955), J. Lab. Clin. Med. 45: 6-17. Elevated levels of aldosterone have been associated with adverse effects on the heart and kidneys, and it has become apparent that it is a major causative factor of morbidity and mortality in heart failure and hypertension.

Two members of the nuclear hormone receptor superfamily, the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR), mediate the function of cortisol in vitro, but the main intracellular receptor for aldosterone is MR. These receptors are also referred to as 'ligand-dependent transcription factors' because their functionality depends on the receptors that bind to their ligands (e.g., cortisol), and when bound to these ligands, these receptors are DNA-binding zinc fingers. Direct transcription is regulated through regions and transcriptional activation regions.

Historically, the major determinants of glucocorticoid action are three: 1) circulating levels of glucocorticoids (primarily driven by the HPA axis), 2) protein binding of glucocorticoids in circulation, and 3) intracellular receptor density inside target tissues. It is considered to be a major factor. Recently, tissue specific receptor prestage metabolism by glucocorticoid activation and inactivation enzymes, the fourth determinant of glucocorticoid function, has been identified. These 11-beta-hydroxysteroid dehydrogenase (11βHSD1) enzymes act as receptor prestage inhibitory enzymes that regulate the activation of GR and MR by the regulation of glucocorticoid hormones. To date, two different isozymes of 11-beta-HSD, 11βHSD1 (also known as 11-beta-HSD type 1, 11betaHSD1, HSD11B1, HDL and HSD11L) and 11βHSD2, have been cloned and characterized. 11βHSD1 and 11βHSD2 catalyze the interconversion of hormone-activated cortisol (rodent corticosterone) and inactive cortisone (rodent 11-dihydrocorticosterone). 11βHSD1 is widely distributed in tissues of rats and humans, so that expression of enzymes and corresponding mRNAs are detected in lungs, testes, and most abundantly in liver and adipose tissue. 11βHSD1 catalyzes both 11-beta-dehydrogenation and reverse 11-oxoreduction reactions, but 11βHSD1 acts primarily as a NADPH-dependent oxolideductase in intact cells and tissues, catalyzing the activation of cortisol from inactive cortisone and [Low et al., (1994) J. mol. Endocrin. 13: 167-174, it has been reported to regulate the access of glucocorticoids to GR. In contrast, 11βHSD2 expression is found primarily in mineralocorticoid target tissues such as kidney, placenta, colon and salivary glands and acts as a NAD-dependent dehydrogenase that catalyzes the inactivation of cortisol to cortisone [Albiston et al. al., (1994) Mol. Cell. Endocrin. 105: R11-R17], has been shown to protect MR from glucocorticoid excesses such as high concentrations of receptor-active cortisol (Blum et al., (2003) Prog. Nucl. Acid Res. Mol. Biol. 75: 173-216.

In vitro, MR binds with equal affinity to cortisol and aldosterone. However, expression of 11βHSD2 confers tissue specificity of aldosterone activity (Funder et al., (1988), Science 242: 583-585). Inactivation of cortisol to cortisone by 11βHSD2 at the MR site enables aldosterone to bind to this receptor in vivo. The binding of aldosterone to MR separates the ligand-activated MR from the polyprotein complex containing chaperone protein, transfers the MR into the nucleus, and binds to hormonal response elements in the regulatory fluid of the target gene promoter. In the distal new unit of the kidney, induction of serum and expression of glucocorticoid-induced kinase-1 (sgk-1) leads to potassium secretion as well as uptake of Na ⁺ ions and water through epithelial sodium channels followed by volumetric expansion and hypertension (Bhargava et al., (2001), Endo 142: 1587-1594).

In humans, elevated aldosterone concentrations are associated with endothelial dysfunction, myocardial infarction, left ventricular atrophy and death. In an attempt to modulate this pathological effect, a number of interventional strategies have been taken to control aldosterone overactivity and reduce hypertension and associated cardiovascular disease. Two strategies that directly affect the Lenin-Angiotensin-Aldosterone family (RAAS) are inhibition of angiotensin converting enzyme (ACE) and blocking of Angiotensin type 1 receptor (AT1R). However, ACE inhibition and AT1R antagonism initially reduce aldosterone concentrations, but in chronic treatment the circulating concentration of this hormone returns to baseline concentrations (known as 'aldosterone excretion'). Importantly, coadministration of MR antagonists, spironolactone or Eplerenone, directly blocks the deleterious effects of this release mechanism and significantly reduces mortality in patients. Pitt el al., New England J. Med. (1999), 341: 709-719; Pitt et al., New England J. Med. (2003), 348: 1309-1321. Thus, MR antagonism may be an important therapeutic strategy for a large number of patients with hypertension and cardiovascular disease, especially for hypertensive patients at risk of target-organ damage.

Mutations in the gene encoding the 11-beta-HSD enzyme are associated with human pathology. For example, 11βHSD2 is expressed in aldosterone-sensitive tissues such as distal new units, salivary glands, and colonic mucosa, where its cortisol dehydrogenase activity protects essentially non-selective MR from unwarranted occupation by cortisol. Edwards et al., (1988) Lancet 2: 986-989. Individuals with mutations of 11βHSD2 lack the activity of this cortisol-inactivation and, as a result, have a clear mineralocorticoid hyperactivity syndrome (also referred to as 'SAME') characterized by hypertension, hypokalemia and sodium retention. Wilson et al., (1998) Proc. Natl. Acad. Sci. 95: 10200-10205. Similarly, mutations of 11βHSD1, a major regulator of tissue-specific glucocorticoid bioactivity, and hexos 6-phosphate dehydrogenase (H6PD), a co-localized NADPH producing enzyme, did not result in activation of cortisone to Cortisol. Corticone reductase deficiency (CRD) can be caused, leading to renocorticotropin-mediated androgen hyperactivity. CRD patients release virtually all glucocorticoids as cortisone metabolites (tetrahydrocortisone) and have no or low concentrations of cortisol metabolites (tetrahydrocortisol). When challenged with oral cortisone, CRD patients exhibit abnormally low plasma cortisol concentrations. These individuals have ACTH-mediated androgen hyperplasia (hirsutism, dysmenorrhea, hyperandrogenosis), phenotype-like polycystic ovary syndrome (PCOS). Draper et al., (2003) Nat. Genet. 34: 434-439.

The importance of the HPA axis in the regulation of glucocorticoid concentrations is evidenced by the fact that disruption of homeostasis of the HPA axis by excessive or deficient secretion or activity leads to Cushing syndrome or Addison disease, respectively. Miller and Chrousos (2001) ) Endocrinology and Metabolism, eds. Felig and Frohman (McGraw-Hill, New York), 4 ^th Ed .: 387-524]. Patients suffering from Cushing's syndrome (a rare disease characterized by excess systemic glucocorticoids resulting from adrenal or pituitary tumors) or undergoing glucocorticoid treatment show recoverable visceral fat obesity. Interestingly, the phenotype of Cushing's syndrome patients is very similar to that of Reaven metabolic syndrome (also known as X syndrome or insulin resistance syndrome), the symptoms of which are visceral obesity, glucose intolerance, insulin resistance, hypertension, type 2 diabetes and Hyperlipidemia, see Reaven (1993) Ann. Rev. Med. 44: 121-131. However, the role of glucocorticoids in the normal form of human obesity is still unknown because circulating glucocorticoid concentrations do not rise in most patients with metabolic syndrome. Indeed, the action of glucocorticoids on target tissues depends not only on circulating concentrations but also on intracellular concentrations, and locally enhanced action of glucocorticoids in adipose tissue and skeletal muscle has been identified in metabolic syndrome. The enzymatic activity of 11βHSD1, which regenerates active glucocorticoids from inactive form and plays a central role in the regulation of intracellular glucocorticoid concentrations, is commonly elevated in fat deposits from obese patients. This suggests a role for local glucocorticoid reactivation in obesity and metabolic syndrome.

Considering the ability of 11βHSD1 to regenerate cortisol from inactive circulating cortisone, considerable attention is paid to its role in the amplification of glucocorticoid function. 11βHSD1 is expressed in a number of important GR-rich tissues, including metabolically significant tissues such as liver, fat and skeletal muscle, and is thought to aid tissue-specific potentiation of glucocorticoid-mediated antagonism of insulin function do. In the X syndrome, taking into account the similarity of the phenotype between glucocorticoid hyperplasia (Cushing syndrome) and metabolic syndrome with normal circulating glucocorticoids, and b) the ability of 11βHSD1 to generate active cortisol in a tissue-specific manner from inactive cortisone Central obesity and related metabolic complications have been suggested to result from increased activity of 11βHSD1 in adipose tissue and cause 'vessel Cushing's disease' (Bujalska et al., (1997) Lancet 349: 1210-1213). Indeed, 11βHSD1 appears to be upregulated in adipose tissue in overly obese rodents and humans. Livingstone et al., (2000) Endocrinology 131: 560-563; Rask et al., (2001) J. Clin. Endocrinol. Metab. 86: 1418-1421; Lindsay et al., (2003) J. Clin. Endocrinol. Metab. 88: 2738-2744; Wake et al., (2003) J. Clin. Endocrinol. Metab. 88: 3983-3988.

Further supporting this fact is the study of mouse transgenic models. Adipose-specific overexpression of 11βHSD1 under the control of the aP2 promoter in mice suggests a phenotype that clearly shows human metabolic syndrome. Masuzaki et al., (2001) Science 294: 2166-2170; Masuzaki et al., (2003) J. Clinical Invest. 112: 83-90. Importantly, this phenotype occurs without an increase in global circulating corticosterone, but rather driven by local production of corticosteroids in fat deposits. The increased activity (11-3 fold) of 11βHSD1 in these mice is very similar to that observed in human obesity. Rask et al., (2001) J. Clin. Endocrinol. Metab. 86: 1418-1421. This suggests that local 11βHSD1-mediated conversion from inactive glucocorticoids to active glucocorticoids can have a significant impact on systemic insulin sensitivity.

Based on these data, the loss of 11βHSD1 is expected to result in increased insulin sensitivity and glucose intolerance due to tissue specific deficiency of active glucocorticoid concentrations. This is in fact the case as shown in studies with 11βHSD1-deficient mice produced by homologous recombination. Kotelevstev et al., (1997) Proc. Natl. Acad. Sci. 94: 14924-14929; Morton et al., (2001) J. Biol. Chem. 276: 41293-41300; Morton et al., (2004) Diabetes 53: 931-938. These mice lack complete 11-keto reductase activity, demonstrating that 11βHSD1 encodes only activity capable of producing active corticosterone from inactive 11-dihydrocorticosterone. 11βHSD1-deficient mice are resistant to diet and stress-induced hyperglycemia, exhibit reduced induction of hepatic glucose angiase (PEPCK, G6P), show increased insulin sensitivity in fat, and improved lipid components ( Reduced triglycerides and increased cardio-protective HDL). In addition, these animals are resistant to high fat diet-induced obesity. Taken together, these transgenic mouse studies demonstrate the role of local reactivation of glucocorticoids in the regulation of hepatic and peripheral insulin sensitivity, and the inhibition of 11βHSD1 activity is associated with a number of glucocorticoids, including obesity, insulin resistance, hyperglycemia and hyperlipidemia. It is suggested that it may be beneficial for the treatment of related disorders.

Data supporting this hypothesis has been published. Recently, 11βHSD1 has been reported to act on the pathology of central obesity and the development of metabolic syndrome in humans. Increased expression of the 11βHSD1 gene is associated with metabolic abnormalities in obese women and increased expression of this gene is thought to contribute to increased local conversion of cortisone to cortisol in the adipose tissue of obese patients. Engeli et al. , (2004) Obes. Res. 12: 9-17.

A new class of 11βHSD1 inhibitors, arylsulfonamidothiazoles, have been shown to improve hepatic insulin sensitivity and reduce blood glucose levels in mice of hyperglycemic strains. Barf et al., (2002) J. Med. Chem. 45: 3813-3815; Alberts et al., Endocrinology (2003) 144: 4755-4762. In addition, it has recently been reported that selective inhibitors of 11βHSD1 can generally alleviate severe hyperglycemia in diabetic obese mice. Thus, 11βHSD1 is a promising pharmaceutical target for the treatment of metabolic syndrome. Masuzaki et al., (2003) Curr. Drug Targets Immune Endocr. Metabol. Disord. 3: 255-62.

A. Obesity and Metabolic Syndrome

As noted above, a number of evidence suggests that inhibition of 11βHSD1 activity may be effective in treating many symptoms of metabolic syndrome, including obesity and / or glucose intolerance, insulin resistance, hyperglycemia, hypertension, and / or hyperlipidemia. Glucocorticoids are known antagonists of insulin action, and a decrease in local glucocorticoid concentration by inhibiting the conversion of intracellular cortisone to cortisol will increase liver and / or peripheral insulin sensitivity and potentially reduce visceral fat. As mentioned above, 11βHSD1 hit mice are resistant to hyperglycemia, show a reduced induction of central hepatic glucose angiogenesis, show markedly increased insulin sensitivity in fat and have an improved lipid profile. In addition, these animals are resistant to high fat diet-induced obesity. Kotelevstev et al., (1997) Proc. Natl. Acad. Sci. 94: 14924-14929; Morton et al., (2001) J. Biol. Chem. 276: 41293- 41300; Morton et al., (2004) Diabetes 53: 931-938. Thus, inhibition of 11βHSD1 is expected to have a number of beneficial effects in the liver, fat, and / or skeletal muscle and in particular be associated with a reduction in metabolic syndrome and / or element (s) of obesity.

B. Pancreatic Function

Glucocorticoids are known to inhibit glucose-stimulated secretion of insulin from pancreatic beta-cells. Billaudel and Sutter (1979) Horm. Metab. Res. 11: 555-560. In Cushing's syndrome and diabetic Zucker fa / fa rats, glucose-stimulated insulin secretion is significantly reduced (Ogawa et al., (1992) J. Clin. Invest. 90: 497-504]. 11βHSD1 mRNA and activity have been reported in islet cells of the pancreas of ob / ob mice, and inhibition of this activity with the 11βHSD1 inhibitor carbenoxolone enhances glucose-stimulated insulin release. Davani et al. (2000) J. Biol. Chem. 275: 34841-34844. Thus, inhibition of 11βHSD1 is expected to provide beneficial effects to the pancreas, including an increase in glucose-stimulated insulin release.

C. Cognitive and Dementia

Mild cognitive impairment is a hallmark of conventional aging and may ultimately be associated with the progression of dementia. In both aged animals and humans, the interpersonal differences in general cognitive function are linked to the variability of long-term exposure to glucocorticoids. Lupien et al., (1998) Nat. Neurosci. 1: 69-73. In addition, dysregulation of the HPA axis resulting in chronic chronic exposure of glucocorticoids in certain brain subregions has been suggested to be a cause of cognitive decline [McEwen and Sapolsky (1995) Curr. Opin. Neurobiol. 5: 205-216. 11βHSD1 is abundant in the brain and expressed in many subregions including the hippocampus, frontal lobe and cerebellum. Sandeep et al., (2004) Proc. Natl. Acad. Sci. Early Edition: 1-6]. Treatment of primary hippocampal cells with 11-HSD1 inhibitor carbenoxolone protects the cells from exacerbation of glucocorticoid-mediated excitatory amino acid neurotoxins. Rajan et al., (1996) J. Neurosci. 16: 65-70. In addition, 11βHSD1-deficient mice are protected from glucocorticoid-related hippocampal dysfunction associated with aging. Yau et al., (2001) Proc. Natl. Acad. Sci. 98: 4716-4721. In two randomized double-blind placebo crossover studies, administration of carbenoxolane improved language fluency and language memory. Sandeep et al., (2004) Proc. Natl. Acad. Sci. Early Edition: 1-6]. Thus, inhibition of 11βHSD1 is expected to reduce glucocorticoid exposure in the brain and protect it from the deleterious effects on neuronal function of glucocorticoids, including cognitive impairment, dementia and / or depression.

D. intraocular pressure

Glucocorticoids can be used locally and systemically for a wide range of clinical ophthalmic diseases. One particular complication in which this therapy is used is glucocorticoid-induced glaucoma. Upper pathology is characterized by a marked rise in intraocular pressure (IOP). In the most advanced state without glaucoma, IOP can cause partial visual field loss and eventually blindness. IOP is created by the correlation between generation and discharge of forward water. Forward water production occurs in non-pigmentary epithelial cells (NPE) and its excretion occurs through the cells of the fibrous line. 11βHSD1 is localized in NPE cells [see Stokes et al., (2000) Invest. Ophthalmol. Vis. Sci. 41: 1629-1683; Rauz et al., (2001) Invest. Ophthalmol. Vis. Sci. 42: 2037-2042] Its function would be associated with an increase in glucocorticoid activity in these cells. This was demonstrated by the fact that the concentration of free cortisol in the forward water was observed to be much higher than that of cortisone (ratio 14: 1). The functional significance of 11βHSD1 in the eye has been assessed using carbenoxolane inhibitors in healthy volunteers. Rauz et al., (2001) Invest. Ophthalmol. Vis. Sci. 42: 2037-2042. After seven days of carbenoxolane treatment, the IOP was reduced by 18%. Thus, inhibition of 11βHSD1 in the eye is expected to reduce local glucocorticoid concentrations and IOPs and have beneficial effects in the treatment of glaucoma and other eye diseases.

E. High Blood Pressure

Adipocyte derived hypertensive substances such as leptin and angiotensinogen have been suggested to be involved in the pathogenesis of obesity-related hypertension. Matsuzawa et al., (1999) Ann. N. Y. Acad. Sci. 892: 146-154; Wajchenberg (2000) Endocr. Rev. 21: 697-738. Over-secreted leptin in aP2-11βHSD1 transgenic mice. Masuzaki et al., (2003) J. Clinical Invest. 112: 83-90] can activate various sympathetic nervous system pathways, including those that regulate blood pressure (Matsuzawa et al., (1999) Ann. N. Y. Acad. Sci. 892: 146-154. In addition, the Lenin-Angiotensin family (RAS) appears to be a major determinant of blood pressure (Walker et al., (1979) Hypertension 1: 287-291). Angiotensinogen, produced in liver and adipose tissue, is an important substrate for renin and promotes RAS activation. Plasma angiotensinogen concentrations are markedly elevated in aP2-11βHSD1 transgenic mice such as angiotensin II and aldosterone. Masuzaki et al., (2003) J. Clinical Invest. 112: 83-90. These forces appear to drive the elevated blood pressure seen in aP2-11βHSD1 transgenic mice. Treatment of these mice with low doses of angiotensin II receptor antagonists eliminates hypertension. Masuzaki et al., (2003) J. Clinical Invest. 112: 83-90. This data speaks of the importance of local glucocorticoid reactivation in adipose tissue and liver and suggests that hypertension can be caused or worsened by 11βHSD1 activity. Thus, inhibition of 11βHSD1 and reduction of fat and / or hepatic glucocorticoid concentrations are expected to have beneficial effects on hypertension and hypertension related cardiovascular disease.

F. Bone Disease

Glucocorticoids can adversely affect skeletal tissue. Even continued exposure to moderate glucocorticoid doses can lead to osteoporosis [Cannalis (1996) J. Clin. Endocrinol. Metab. 81: 3441-3447] The risk of fracture is increased. In vitro experiments have confirmed the deleterious effects of glucocorticoids on both bone resorption cells (also known as osteoclasts) and osteoblasts (osteoblasts). 11βHSD1 appears to exist in cultures of primary osteoblasts in humans as well as in cells derived from adult bone, possibly a mixture of osteoclasts and osteoblasts (Cooper et al., (2000) Bone 27: 375-381), Carbenoxolane, an 11βHSD1 inhibitor, appears to reduce the deleterious effects of glucocorticoids on bone nodule formation (Bellows et al., (1998) Bone 23: 119-125). Thus, inhibition of 11βHSD1 is expected to reduce local glucocorticoid concentrations in osteoblasts and osteoclasts, providing beneficial efficacy for various forms of bone disease, including osteoporosis.

Currently, small molecule inhibitors of 11βHSD1 are under development for the treatment or prevention of 11βHSD1 related diseases as described above. For example, certain amide-based inhibitors have been reported in International Publications WO 2004/089470, WO 2004/089896, WO 2004/056745 and WO 2004/065351.

Antagonists of 11βHSD1 have been evaluated in human clinical studies. Kurukulasuriya et al., (2003) Curr. Med. Chem. 10: 123-53.

Experimental showing the action of 11βHSD1 in glucocorticoid related diseases metabolic syndrome, hypertension, obesity, insulin resistance, hyperglycemia, hyperlipidemia, type 2 diabetes, hyperandrogenosis (hirsutism, dysmenorrhea, hyperandrogenosis) and polycystic ovary syndrome (PCOS) In view of the data, therapeutic agents aimed at augmenting or inhibiting these metabolic pathways by modulating glucocorticoid signal transduction at the level of 11βHSD1 are preferred.

In addition, since MR binds with equal affinity to aldosterone (its essential ligand) and cortisol, compounds designed to interact with the active site of 11βHSD1 (binding to cortisone / cortisol) can also interact with MR and act as antagonists. MR antagonists are preferred because MR has been implicated in heart failure, hypertension, and related pathologies including atherosclerosis, atherosclerosis, coronary artery disease, thrombosis, angina pectoris, peripheral vascular disease, vascular wall damage, and stroke. Lipidemia, hyperlipoproteinemia, diabetic dyslipidemia, mixed dyslipidemia, hypercholesterolemia, hypertriglyceridemia, and type 1 diabetes, type 2 diabetes, obesity, metabolic syndrome, insulin resistance and general aldosterone-related It may also be useful in the treatment of complex cardiovascular, renal and inflammatory pathologies, including lipid metabolism disorders such as target organ damage.

As demonstrated herein, there is a continuing need for new and improved drugs targeting 11βHSD1 and / or MR. The compounds, compositions and methods described herein meet these and other needs.

Summary of the Invention

The present invention particularly provides a compound of formula (Ia) or a pharmaceutically acceptable salt or prodrug thereof, wherein the member is defined herein.

The present invention further provides a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof, wherein the member is defined herein.

The invention further provides a method of modulating 11βHSD1 or MR by contacting 11βHSD1 or MR with a compound of the present invention.

The invention further provides a method of inhibiting 11-β-HSD1 or MR by contacting 11βHSD1 or MR with a compound of the present invention.

The invention further provides a method of inhibiting the conversion of cortisone to cortisol in a cell.

The invention further provides a method of inhibiting cortisol production in a cell by contacting the cell with a compound of the invention.

The invention further provides a method of treating a disease associated with the activity or expression of 11βHSD1 or MR.

The invention further provides a compound of the invention for use in therapy.

The invention further provides a compound of the invention for use in the manufacture of a therapeutic medicament.

The present invention provides the general formula (Ia) or a pharmaceutically acceptable salt or prodrug thereof.

Formula Ia

In Formula Ia,

L is absent or S (O) ₂ , S (O), S, C (O), C (O) O, C (O) O- (C _1-3 alkylene) or C (O) NR ^L ego;

Ar is aryl or heteroaryl, optionally substituted by 1, 2, 3, 4 or 5 W-X-Y-Z, respectively;

R ^L is H or C _1-6 alkyl;

R ¹ is H, C (O) OR ^{b '} , S (O) R ^a' , S (O) NR ^{c '} R ^d' , S (O) ₂ R ^{a '} , S (O) ₂ NR ^c' R ^{d '} , C _1-10 alkyl, C _1-10 haloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cyclo Alkylalkyl or heterocycloalkylalkyl, wherein C _1-10 alkyl, C _1-10 haloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, Arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 or 3 R ¹⁴ ;

R ² is each H, C _1-6 alkyl, arylalkyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl, optionally substituted by 1, 2 or 3 R ¹⁴ ;

R ³ is each H, C _1-6 alkyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl optionally substituted by 1, 2 or 3 W′-X′-Y′-Z ′;

R ³ is NR ^3a R ^3b ;

R ^3a and R ^3b are each independently H, C _1-6 alkyl, aryl, cycloalkyl, heteroaryl or hetero optionally substituted by 1, 2 or 3 W'-X'-Y'-Z ', respectively Cycloalkyl;

R ^3a and R ^3b together with the N atom to which they are attached form a 4-14 membered heterocycloalkyl group optionally substituted by 1, 2 or 3 W'-X'-Y'-Z ';

R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each independently H, OC (O) R ^{a '} , OC (O) OR ^b' , C (O) OR ^{b '} , OC (O) NR ^c' R ^{d '} , NR ^c' R ^{d '} , NR ^c' C (O) R ^{a '} , NR ^c' C (O) OR ^{b '} , S (O) R ^a' , S (O) NR ^{c '} R ^d' , S (O) ₂ R ^{a '} , S (O) ₂ NR ^c' R ^{d '} , SR ^b' , C _1-10 alkyl, C _1-10 haloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C _1-10 alkyl , C _1-10 haloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl Optionally substituted by 1, 2 or 3 R ¹⁴ ; or

R ¹ and R ² together with the carbon and nitrogen atoms to which they are attached form a 3 to 14 membered heterocycloalkyl group optionally substituted by 1, 2 or 3 R ¹⁴ ;

R ¹ and R ³ together with the carbon atom to which they are attached and the intervening —NR ² CO— moiety form a 4 to 14 membered heterocycloalkyl group optionally substituted by 1, 2 or 3 R ¹⁴ ;

R ² and R ³ together with the carbon and nitrogen atoms to which they are attached form a 3 to 14 membered heterocycloalkyl group optionally substituted by 1, 2 or 3 R ¹⁴ ;

R ⁴ and R ⁵ together with the carbon atom to which they are attached form a 3- to 14-membered cycloalkyl or heterocycloalkyl group optionally substituted by 1, 2 or 3 R ¹⁴ ;

Or R ⁶ and R ⁷ together with the carbon atom to which they are attached form a 3 to 14 membered cycloalkyl or heterocycloalkyl group optionally substituted by 1, 2 or 3 R ¹⁴ ;

R ⁸ and R ⁹ together with the carbon atom to which they are attached form a 3- to 14-membered cycloalkyl or heterocycloalkyl group optionally substituted by 1, 2 or 3 R ¹⁴ ;

R ¹⁰ and R ¹¹ together with the carbon atom to which they are attached form a 3- to 14-membered cycloalkyl or heterocycloalkyl group optionally substituted by 1, 2 or 3 R ¹⁴ ;

R ⁴ and R ⁶ together with the carbon atom to which they are attached are a 3-7 membered fused cycloalkyl group or 3-7 membered fused heterocyclo optionally substituted by 1, 2 or 3 R ¹⁴ To form an alkyl group;

R ⁶ and R ⁸ together with the carbon atom to which they are attached are a 3-7 membered fused cycloalkyl group or a 3-7 membered fused heterocyclo optionally substituted by 1, 2 or 3 R ¹⁴ To form an alkyl group;

R ¹⁴ is halo, C _1-4 alkyl, C _1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO ₂ , OR ^{a '} , SR ^a' , C (O) R ^{b '} , C (O) NR ^{c '} R ^d' , C (O) OR ^{a '} , OC (O) R ^b' , OC (O) NR ^{c '} R ^d' , NR ^{c '} R ^d' , NR ^{c '} C (O) R ^{d '} , NR ^c' C (O) OR ^{a '} , S (O) R ^b' , S (O) NR ^{c '} R ^d' , S (O) ₂ R ^{b '} or S (O) ₂ NR ^{c '} R ^d' ;

W, W 'and W "are each independently absent or C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynylenyl, O, S, NR ^e , CO, COO, CONR ^e , SO, SO ₂ , SONR ^e or NR ^e CONR ^f , wherein C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynylenyl are each 1, 2 or 3 halo, Optionally substituted by OH, C _1-4 alkoxy, C _1-4 haloalkoxy, amino, C _1-4 alkylamino or C _2-8 dialkylamino;

X, X 'and X "are each independently absent or C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynenyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl Wherein C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynylenyl, cycloalkyl, heteroaryl or heterocycloalkyl is one or more halo, CN, NO ₂ , OH, C _1- Optionally substituted by ₄ alkoxy, C _1-4 haloalkoxy, amino, C _1-4 alkylamino or C _2-8 dialkylamino;

Y, Y 'and Y "are each independently, absent or C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynylenyl, O, S, NR ^e , CO, COO, CONR ^e , SO, SO ₂ , SONR ^e or NR ^e CONR ^f , wherein C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynylenyl are each 1, 2 or 3 halo, Optionally substituted by OH, C _1-4 alkoxy, C _1-4 haloalkoxy, amino, C _1-4 alkylamino or C _2-8 dialkylamino;

Z, Z 'and Z "are each independently H, halo, CN, NO ₂ , OH, C _1-4 alkoxy, C _1-4 haloalkoxy, amino, C _1-4 alkylamino or C _2-8 dialkyl Amino, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl may be 1, 2 or 3 halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{1- 4} haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO ₂ , OR ^a , SR ^a , C (O) R ^b , C (O) NR ^c R ^d , C (O) OR ^a , OC (O) R ^b , OC (O) NR ^c R ^d , NR ^c R ^d , NR ^c C (O) R ^d , NR ^c C (O) OR ^a , S (O) R ^b , S (O) Optionally substituted by NR ^c R ^d , S (O) ₂ R ^b or S (O) ₂ NR ^c R ^d ,

Wherein two -WXYZs bonded to the same atom each represent a 3-14 membered cycloalkyl or heterocycloalkyl group optionally substituted by 1, 2 or 3 -W "-X" -Y "-Z" Optionally form;

Wherein two -W'-X'-Y'-Z's bonded to the same atom are each three to fourteen, optionally substituted by one, two or three -W "-X" -Y "-Z"; Optionally forms a cycloalkyl or heterocycloalkyl group;

Wherein -W-X-Y-Z is not H;

Wherein -W'-X'-Y'-Z 'is not H;

Wherein -W "-X" -Y "-Z" is not H;

R ^a and R ^{a '} are each independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocyclo Alkyl, wherein C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl; Heterocycloalkyl, heterocycloalkylalkyl is selected from H, OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl Optionally substituted;

R ^b and R ^{b ′} are each independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl , Arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cyclo Alkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is H, OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 Optionally substituted by haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;

R ^c and R ^d are each independently H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl , Arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, hetero Aryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is H, OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 Optionally substituted by haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or

R ^c and R ^d together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group;

R ^{c '} and R ^d' are each independently H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclo Alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, Heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is H, OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1- Optionally substituted by ₆ haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or

R ^{c '} and R ^d' together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group;

R ^e and R ^f are each independently H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, Arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl , Cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is H, OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 halo Optionally substituted by alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or

R ^e and R ^f together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group;

q is 1 or 2.

In some embodiments, when L is absent and R ² is methyl, R ³ is not C _2-3 alkyl substituted by S (O) ₂ R ^b .

In some embodiments, when L is absent and R ³ is methyl, R ² is not ethyl substituted by NR ^{c ′} R ^{d ′} .

In some embodiments, when L is S (O) ₂ and Ar is 4-methylphenyl, R ³ is not piperazin-1-yl 4-substituted by aryl.

In some embodiments, when L is S (O) ₂ and q is 2, Ar is not aryl optionally substituted by 1, 2, 3, 4 or 5 WXYZ.

In some embodiments, when L is C (O) NH and Ar is phenyl substituted by COOH, R ³ is heteroaryl or two W 'substituted by two W'-X'-Y'-Z'. It is not ethyl substituted by -X'-Y'-Z '.

In some embodiments, when L is C (O), C (O) O or C (O) O- (C _1-3 alkylene), R ³ is substituted or unsubstituted piperidin-3-yl. no.

In some embodiments, when L is C (O), C (O) O or C (O) O- (C _1-3 alkylene), R ³ is not substituted or unsubstituted piperidinyl.

In some embodiments, R ³ is piperidin-3-yl N-substituted by one C (O)-(C _1-4 alkyl) or one C (O) O (C _1-4 alkyl) no.

In some embodiments, R ³ is not N-substituted piperidin-3-yl.

In some embodiments, R ³ is not N-substituted pyrrolidin-3-yl.

In some embodiments, R ³ is not substituted piperidin-3-yl.

In some embodiments, R ³ is not substituted pyrrolidin-3-yl.

In some embodiments, R ³ is not substituted piperidinyl.

In some embodiments, R ³ is not substituted pyrrolidinyl.

In some embodiments, R ³ is not substituted 6 membered heterocycloalkyl.

In some embodiments, L is absent or is S (O) ₂ , C (O) NR ^L or C (O) O— (C _1-3 alkylene).

In some embodiments, L is absent or S (O) ₂ or C (O) NR ^L.

In some embodiments, L is absent or S (O) ₂ .

In some embodiments, L is S (O) ₂ .

In some embodiments, L is absent.

In some embodiments, L is C (O).

In some embodiments, L is C (O) NR ^L.

In some embodiments, L is C (O) NH.

In some embodiments, L is C (O) O— (C _1-3 alkylene).

In some embodiments, L is C (O) O—CH ₂ .

In some embodiments, the compound is a compound of Formula IIa

In some embodiments, the compound is a compound of Formula IIa and Ar is phenyl, pyridyl, pyrimidinyl, or thiazolyl, optionally substituted by one or two W-X-Y-Z, respectively.

In some embodiments, the compound is a compound of Formula IIa and Ar is 1 or 2 halo, nitro, cyano, amino, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 Haloalkoxy, dialkylaminocarbonyl, dialkylaminocarbonylalkyloxy, cycloalkylcarbonylamino, cycloalkylcarbonyl (alkyl) amino, alkoxycarbonylamino, alkoxycarbonyl, alkylsulfonyl, alkylsulfonylamino, Cycloalkylalkylcarbonylamino, aryl, heteroaryl, heterocycloalkyl, arylalkyloxy, cycloalkyloxy, heterocycloalkyloxy, acylamino, acyl (alkyl) amino; 1,2,3,6-tetrahydropyridinyl substituted by alkoxycarbonyl; Phenyl, pyridyl, pyrimidinyl or thiazolyl optionally substituted by 2-oxopiperidinyl or 2-oxopyrrolidinyl,

Wherein aryl, heteroaryl, heterocycloalkyl and heterocycloalkyloxy are each one or more halo, cyano, C _1-4 alkoxy, acyl, acylamino, alkylsulfonyl, cycloalkylaminocarbonyl, alkoxycarbonyl or amino Optionally substituted by carbonyl.

In some embodiments, the compound is a compound of Formula IIa and R ³ is each cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, optionally substituted by one or two W'-X'-Y'-Z ', Adamantyl, bicyclo [3.2.1] octanyl, norbornyl, 1,2,3,4-tetrahydronaphthyl, azepan-7-one-yl, 8-aza-bicyclo [3.2.1 ] Octanyl, indolyl, quinolinyl, indol-3-ylmethyl or phenyl.

In some embodiments, the compound is a compound of Formula IIa and R ³ is 1 or 2 halo, OH, C _1-4 alkyl, C _1-4 alkoxy, hydroxylalkyl, aryl, aryloxy, heteroaryl, heteroarylalkyl Or cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, bicyclo [3.2.1] octanyl, norbornyl, 1,2,3,4 optionally substituted by alkylcarbonyloxy Tetrahydronaphthyl, azepan-7-one-yl, 8-aza-bicyclo [3.2.1] octanyl or phenyl,

Wherein aryl, heteroaryl, heteroarylalkyl is optionally substituted by one or two C _1-4 alkyl or heterocycloalkyl optionally substituted by alkoxycarbonyl.

In some embodiments, the compound is a compound of Formula IIIa.

In some embodiments, the compound is formula IVa.

In some embodiments, the compound is a compound of Formula Va.

In some embodiments, the compound is a compound of Formula Va. In some embodiments of compounds of Formula IV, when Ar is phenyl substituted by COOH, R ³ is heteroaryl substituted by two W'-X'-Y'-Z 'or two W'-X' It is not ethyl substituted by -Y'-Z '.

In some embodiments, the compound is a compound of Formula (I) or a pharmaceutically acceptable salt or prodrug thereof.

Formula I

In Formula I,

Ar is aryl or heteroaryl, optionally substituted by 1, 2, 3, 4 or 5 W-X-Y-Z, respectively;

R ¹ is H, C (O) OR ^{b '} , S (O) R ^a' , S (O) NR ^{c '} R ^d' , S (O) ₂ R ^{a '} , S (O) ₂ NR ^c' R ^{d '} , C _1-10 alkyl, C _1-10 haloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cyclo Alkylalkyl or heterocycloalkylalkyl, wherein C _1-10 alkyl, C _1-10 haloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, Arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 or 3 R ¹⁴ ;

R ² is each H, C _1-6 alkyl, arylalkyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl, optionally substituted by 1, 2 or 3 R ¹⁴ ;

R ³ is each H, C _1-6 alkyl, aryl, cycloalkyl or heteroaryl, optionally substituted by 1, 2 or 3 W'-X'-Y'-Z ';

R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each independently H, OC (O) R ^{a '} , OC (O) OR ^b' , C (O) OR ^{b '} , OC (O) NR ^c' R ^{d '} , NR ^c' R ^{d '} , NR ^c' C (O) R ^{a '} , NR ^c' C (O) OR ^{b '} , S (O) R ^a' , S (O) NR ^{c '} R ^d' , S (O) ₂ R ^{a '} , S (O) ₂ NR ^c' R ^{d '} , SR ^b' , C _1-10 alkyl, C _1-10 haloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C _1-10 alkyl , C _1-10 haloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl Optionally substituted by 1, 2 or 3 R ¹⁴ ; or

R ¹ and R ² together with the carbon and nitrogen atoms to which they are attached form a 3 to 14 membered heterocycloalkyl group optionally substituted by 1, 2 or 3 R ¹⁴ ;

R ¹ and R ³ together with the carbon atom to which they are attached and the intervening —NR ² CO— moiety form a 4 to 14 membered heterocycloalkyl group optionally substituted by 1, 2 or 3 R ¹⁴ ;

R ² and R ³ together with the carbon and nitrogen atoms to which they are attached form a 3 to 14 membered heterocycloalkyl group optionally substituted by 1, 2 or 3 R ¹⁴ ;

R ⁴ and R ⁵ together with the carbon atom to which they are attached form a 3 to 14 membered cycloalkyl or 3 to 14 membered heterocycloalkyl group optionally substituted by 1, 2 or 3 R ¹⁴ ;

R ⁶ and R ⁷ together with the carbon atom to which they are attached form a 3 to 14 membered cycloalkyl or 3 to 14 membered heterocycloalkyl group optionally substituted by 1, 2 or 3 R ¹⁴ ;

R ⁸ and R ⁹ together with the carbon atom to which they are attached form a 3 to 14 membered cycloalkyl or 3 to 14 membered heterocycloalkyl group optionally substituted by 1, 2 or 3 R ¹⁴ ;

R ¹⁰ and R ¹¹ together with the carbon atom to which they are attached form a 3 to 14 membered cycloalkyl or 3 to 14 membered heterocycloalkyl group optionally substituted by 1, 2 or 3 R ¹⁴ ;

R ⁴ and R ⁶ together with the carbon atom to which they are attached are a 3-7 membered fused cycloalkyl group or 3-7 membered fused heterocyclo optionally substituted by 1, 2 or 3 R ¹⁴ To form an alkyl group;

R ⁶ and R ⁸ together with the carbon atom to which they are attached are a 3-7 membered fused cycloalkyl group or a 3-7 membered fused heterocyclo optionally substituted by 1, 2 or 3 R ¹⁴ To form an alkyl group;

R ¹⁴ is halo, C _1-4 alkyl, C _1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO ₂ , OR ^{a '} , SR ^a' , C (O) R ^{b '} , C (O) NR ^{c '} R ^d' , C (O) OR ^{a '} , OC (O) R ^b' , OC (O) NR ^{c '} R ^d' , NR ^{c '} R ^d' , NR ^{c '} C (O) R ^{d '} , NR ^c' C (O) OR ^{a '} , S (O) R ^b' , S (O) NR ^{c '} R ^d' , S (O) ₂ R ^{b '} or S (O) ₂ NR ^{c '} R ^d' ;

W, W 'and W "are each independently absent or C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynylenyl, O, S, NR ^e , CO, COO, CONR ^e , SO, SO ₂ , SONR ^e or NR ^e CONR ^f , wherein C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynylenyl are 1, 2 or 3 halo, OH Optionally substituted by C _1-4 alkoxy, C _1-4 haloalkoxy, amino, C _1-4 alkylamino or C _2-8 dialkylamino;

X, X 'and X "are each independently absent or C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynenyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl Where C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynylenyl, cycloalkyl, heteroaryl or heterocycloalkyl is one or more halo, CN, NO ₂ , OH, C ₁ Optionally substituted by _-4 alkoxy, C _1-4 haloalkoxy, amino, C _1-4 alkylamino or C _2-8 dialkylamino;

Y, Y 'and Y "are each independently absent or C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynylenyl, O, S, NR ^e , CO, COO, CONR ^e , SO, SO ₂ , SONR ^e or NR ^e CONR ^f , wherein C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynylenyl are each 1, 2 or 3 halo, OH Optionally substituted by C _1-4 alkoxy, C _1-4 haloalkoxy, amino, C _1-4 alkylamino or C _2-8 dialkylamino;

Z, Z 'and Z "are each independently H, halo, CN, NO ₂ , OH, C _1-4 alkoxy, C _1-4 haloalkoxy, amino, C _1-4 alkylamino or C _2-8 dialkyl Amino, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl may be 1, 2 or 3 halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{1- 4} haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO ₂ , OR ^a , SR ^a , C (O) R ^b , C (O) NR ^c R ^d , C (O) OR ^a , OC (O) R ^b , OC (O) NR ^c R ^d , NR ^c R ^d , NR ^c C (O) R ^d , NR ^c C (O) OR ^a , S (O) R ^b , S (O) Optionally substituted by NR ^c R ^d , S (O) ₂ R ^b , or S (O) ₂ NR ^c R ^d ,

Wherein two W-X-Y-Z bonded to the same atom optionally form a 3- to 14-membered cycloalkyl or heterocycloalkyl group optionally substituted by 1, 2 or 3 W "-X" -Y "-Z";

Wherein two W'-X'-Y'-Z 'bonded to the same atom are 3- to 14-membered cycloalkyl optionally substituted by 1, 2 or 3 W "-X" -Y "-Z" Or optionally forms a heterocycloalkyl group;

Wherein W-X-Y-Z is not H;

Wherein W'-X'-Y'-Z 'is not H;

Wherein W "-X" -Y "-Z" is not H;

R ^a and R ^{a '} are each independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocyclo Alkyl, wherein C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl; Heterocycloalkyl, heterocycloalkylalkyl is selected from H, OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl Optionally substituted;

R ^b and R ^{b ′} are each independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclo Alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, Cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is H, OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1- Optionally substituted by ₆ haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl;

R ^c and R ^d are each independently H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, Arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl , Cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is H, OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 halo Optionally substituted by alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or

R ^c and R ^d together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group;

R ^{c '} and R ^d' are each independently H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclo Alkyl, arylalkyl, hetero arylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, Heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is H, OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1- Optionally substituted by ₆ haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or

R ^{c '} and R ^d' together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group;

R ^e and R ^f are each independently H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl , Arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, hetero Aryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is H, OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 Optionally substituted by haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or

R ^e and R ^f together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group;

q is 1 or 2.

In some embodiments, Ar is aryl optionally substituted by 1, 2, 3, 4 or 5 W-X-Y-Z.

In some embodiments, Ar is aryl optionally substituted by 1, 2 or 3 -Z.

In some embodiments, Ar is optionally substituted phenyl or naphthyl by 1, 2, 3, 4 or 5 W-X-Y-Z, respectively.

In some embodiments, Ar is phenyl or naphthyl, optionally substituted by 1, 2 or 3 -Z, respectively.

In some embodiments, Ar is 1, 2 or 3 halo; Nitro; Cyano; C _{1 -4} alkyl; C _{1 -4} haloalkyl; C _{1 -4} alkoxy; C _{1 -4} haloalkoxy; Dialkylamino; Dialkylaminocarbonyl; Alkylsulfonyl; Cycloalkyloxy; Heteroaryloxy; Aryloxy; Cycloalkyl; Heterocycloalkyl; Phenyl optionally substituted by one or more halo, cyano, C _1-4 alkyl, C _1-4 alkoxy or —NHC (O) — (C _1-4 alkyl); Or one or more halo, cyano, C _1-4 alkyl, C _1-4 alkoxy, or _{-NHC (O) - (C 1} -4 alkyl) in an optionally substituted pyridyl, optionally substituted in the phenyl or naphthyl by by .

In some embodiments, Ar is 1, 2 or 3 halo, nitro, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, —O-aryl , -O-heteroaryl, phenyl or naphthyl optionally substituted by NHC (O)-(C _1-4 alkyl) or SO _2- (C _1-4 alkyl).

In some embodiments, Ar is phenyl or naphthyl, optionally substituted by 1, 2 or 3 C _1-4 alkyl or aryloxy, respectively.

In an embodiment Ar is heteroaryl optionally substituted by 1, 2, 3, 4 or 5 W-X-Y-Z.

In some embodiments, Ar is heteroaryl optionally substituted by 1, 2 or 3 -Z.

In some embodiments, Ar is pyridyl, pyrimidinyl, thienyl, thiazolyl, quinolinyl, 2,1,3-benzoxadiazolyl optionally substituted by 1, 2, 3, 4 or 5 WXYZ, respectively , Isoquinolinyl or isoxazolyl.

In some embodiments, Ar is pyridyl, thienyl, or isoxazolyl optionally substituted by 1, 2, 3, 4 or 5 W-X-Y-Z, respectively.

In some embodiments, Ar is pyridyl, quinolinyl, 2,1,3-benzoxadiazolyl, isoquinolinyl, thienyl or isoxazolyl, each optionally substituted by 1, 2 or 3 -Z .

In some embodiments, Ar is pyridyl, thienyl or isoxazolyl optionally substituted by 1, 2 or 3 -Z, respectively.

In some embodiments, Ar is pyridyl, quinolinyl, 2,1,3-benzoxadiazolyl, isoquinolinyl optionally substituted by 1, 2 or 3 halo, C _1-4 alkyl or aryloxy, respectively , Thienyl or isoxazolyl.

In some embodiments q is 1.

In some embodiments, -WXYZ is halo, nitro, cyano, OH, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, amino, C _1-4 alkoxy, cycloalkylcarbonylamino, Alkoxycarbonylamino, alkylsulfonylamino, cycloalkylalkylcarbonylamino, acyl (alkyl) amino, alkylamino, dialkylamino, dialkylaminosulfonyl, dialkylaminocarbonyl, dialkylaminocarbonylalkyloxy, Alkylcarbonyl (alkyl) amino, cycloalkylcarbonyl (alkyl) amino, alkoxycarbonyl (alkyl) amino, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, aryl 1,2,3,6-tetrahydropyridinyl, 2-oxopiperidinyl or 2 substituted by oxy, cycloalkyloxy, heteroaryloxy, heterocycloalkyloxy, arylalkyloxy, acylamino, alkoxycarbonyl Oxopyrrolidinyl,

Wherein aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyloxy or heterocycloalkyloxy is one or more halo, C _1-4 alkyl, OH, C _1-4 alkoxy, cycloalkylaminocarbonyl, alkoxycarbonyl Optionally substituted with cyano, acyl, acylamino, alkylsulfonyl, amino, alkylamino, dialkylamino or aminocarbonyl.

In some embodiments, -W'-X'-Y'-Z 'is halo, OH, cyano, nitro, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 halo Alkoxy, amino, alkylamino, dialkylamino, hydroxylalkyl, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocycloalkylalkyl, Heterocycloalkylalkyl, heterocycloalkyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonyloxy, alkylsulfonyl or arylsulfonyl,

Wherein aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocycloalkylalkyl, heterocycloalkylalkyl or heterocycloalkyloxy is 1 or 2 Halo, OH, cyano, nitro, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, amino, alkylamino, dialkylamino, hydroxyalkyl, or Optionally substituted by alkoxycarbonyl.

In some embodiments, -W "-X" -Y "-Z" is halo, OH, cyano, nitro, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 halo Alkoxy, amino, alkylamino, dialkylamino, hydroxylalkyl, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocycloalkylalkyl, Heterocycloalkylalkyl, heterocycloalkyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonyloxy, alkylsulfonyl or arylsulfonyl.

In some embodiments q is 1.

In some embodiments, R ³ is C _1-6 alkyl optionally substituted by 1, 2 or 3 W'-X'-Y'-Z '.

In some embodiments, R ³ is C _1-6 alkyl optionally substituted by 1 or 2 aryl.

In some embodiments, R ³ is C _1-6 alkyl.

In some embodiments, R ³ is aryl, cycloalkyl, heteroaryl or heterocycloalkyl, each optionally substituted by 1, 2 or 3 W′-X′-Y′-Z ′.

In some embodiments, R ³ is aryl, cycloalkyl, or heteroaryl, optionally substituted by one, two, or three W′-X′-Y′-Z ′, respectively.

In some embodiments, R ³ is 1, 2 or 3 halo, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, phenyl, halo-substituted phenyl, phenyloxy, pyridyl, acyl , Alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, or C _1-4 alkyl, aryl, cycloalkyl, hetero optionally substituted by arylsulfonyl optionally substituted by 1 or 2 halo or C _1-4 alkyl Aryl or heterocycloalkyl.

In some embodiments, R ³ is 1, 2 or 3 halo, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _2-8 alkoxyalkyl, phenyl , Aryl, cycloalkyl or heteroaryl, optionally substituted by phenyloxy, pyridyl or azepan-2-one-yl.

In some embodiments, R ³ is aryl or cycloalkyl, optionally substituted by 1, 2 or 3 W'-X'-Y'-Z ', respectively.

In some embodiments, R ³ is cycloheptyl, cyclohexyl, cyclopentyl, cyclopropyl, 1,2,3,4- optionally substituted by 1, 2 or 3 W'-X'-Y'-Z ', respectively. Tetrahydronaphthalenyl, norbornyl or adamantyl.

In some embodiments, R ³ is cycloheptyl, cyclohexyl, cyclopentyl, cyclopropyl or adamantyl, each optionally substituted by 1, 2 or 3 W′-X′-Y′-Z ′.

In some embodiments, R ³ is cycloheptyl, cyclohexyl, cyclopentyl, cyclopropyl, or adamantyl, each optionally substituted by 1, 2 or 3 -Z '.

In some embodiments, R ³ is cycloheptyl, cyclohexyl, cyclopentyl, each optionally substituted by 1, 2 or 3 CN, OH, C _1-4 alkoxy, C _1-6 alkyl, aryl or halo-substituted aryl , Cyclopropyl or adamantyl.

In some embodiments, R ³ is cycloheptyl, cyclohexyl, cyclopentyl, cyclo optionally substituted with 1, 2 or 3 OH, C _1-4 alkoxy, C _1-6 alkyl, aryl or halo-substituted aryl, respectively Propyl or adamantyl.

In some embodiments, R ³ is adamantyl optionally substituted by OH.

In some embodiments, R ³ is phenyl or naphthyl, optionally substituted by 1, 2 or 3 W'-X'-Y'-Z ', respectively.

In some embodiments, R ³ is phenyl or naphthyl, optionally substituted by 1, 2 or 3 -Z ', respectively.

In some embodiments, R ³ is 1, 2 or 3 halo, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _2-8 alkoxyalkyl, aryl , Phenyl or naphthyl optionally substituted by aryloxy, pyridyl or azepan-2-one-yl.

In some embodiments, R ³ is phenyl or naphthyl, optionally substituted by 1, 2 or 3 halo, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, aryl or aryloxy.

In some embodiments, R ³ is heteroaryl or heterocycloalkyl, each optionally substituted by 1, 2 or 3 W′-X′-Y′-Z ′.

In some embodiments, R ³ is piperidinyl optionally substituted by 1, 2 or 3 W'-X'-Y'-Z '.

In some embodiments, R ³ is piperidinyl optionally substituted by 1, 2 or 3 Z ′.

In some embodiments, R ³ is 1, 2 or 3 CO- (C _1-4 alkyl), C (O) O- (C _1-4 alkyl), SO _2- (C _1-4 alkyl), SO ₂ Piperidinyl optionally substituted by -aryl or SO _2- (aryl substituted with one or two halo or C _1-4 alkyl).

In some embodiments, R ³ is 1, 2 or 3 SO _2- (C _1-4 alkyl), SO ₂ -aryl or SO _2- (aryl substituted by 1 or 2 halo or C _1-4 alkyl) Piperidinyl optionally substituted by.

In some embodiments, R ³ is pyridyl optionally substituted by 1, 2 or 3 W'-X'-Y'-Z '.

In some embodiments, R ³ is pyridyl optionally substituted by 1, 2 or 3 Z ′.

In some embodiments, R ³ is pyridyl.

In some embodiments, R ³ is 8-aza-bicyclo [3.2.1] octanyl, indolyl, morpholino, optionally substituted by 1, 2 or 3 W'-X'-Y'-Z ', respectively. , S-oxo-thiomorpholino, S, S-dioxo-thiomorpholino or thiomorpholino.

In some embodiments, R ³ is 8-aza-bicyclo [3.2.1] octanyl, indolyl, morpholino, S-oxo-thiomorpholi, optionally substituted by 1, 2 or 3 -Z ', respectively. Furnace, S, S-dioxo-thiomorpholino or thiomorpholino.

In some embodiments, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each H.

In some embodiments, R ¹ is H.

In some embodiments, R ² is H.

In some embodiments, the compound is a compound of Formula (II).

In some embodiments, the compound is a compound of Formula II, and Ar is one or two halo, cyano, nitro, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 halo Phenyl, naphthyl, pyridyl, thienyl, isoxazolyl, quinolinyl, isoquinolinyl or 2 optionally substituted by alkoxy, aryloxy, heteroaryloxy, acylamino, alkylsulfonyl, or dialkylamino , 1,3-benzoxadiazolyl.

In some embodiments, the compound is a compound of Formula II and R ³ is C _1-4 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, each substituted by one or two OH Phenyl, naphthyl, pyridyl, piperidinyl, morpholino, S-oxo-thiomorpholino, S, S-dioxo-thiomorpholino, thiomorpholino or 8-aza-bicyclo [3.2 .1] octanyl; C _1-4 alkyl; C _1-4 alkoxy; C _1-4 haloalkyl; Phenyl; Phenyloxy; Arylsulfonyl optionally substituted by 1 or 2 halo or C _1-4 alkyl; Chlorophenyl; Alkylcarbonyl; Alkoxycarbonyl; Or alkylsulfonyl.

In some embodiments, the compound is

Ar is aryl or heteroaryl, optionally substituted by 1, 2, 3, 4 or 5 W-X-Y-Z, respectively;

R ¹ is H, C (O) OR ^{b '} , S (O) R ^a' , S (O) NR ^{c '} R ^d' , S (O) ₂ R ^{a '} , S (O) ₂ NR ^c' R ^{d '} , C _1-10 alkyl, C _1-10 haloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cyclo Alkylalkyl or heterocycloalkylalkyl, wherein C _1-10 alkyl, C _1-10 haloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, Arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 or 3 R ¹⁴ ;

R ² is H or C _1-6 alkyl;

R ³ is each H, C _1-6 alkyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl optionally substituted by 1, 2 or 3 W'-X'-Y'-Z ';

R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each independently H, OC (O) R ^{a '} , OC (O) OR ^b' , C (O) OR ^{b '} , OC (O) NR ^c' R ^{d '} , NR ^c' R ^{d '} , NR ^c' C (O) R ^{a '} , NR ^c' C (O) OR ^{b '} , S (O) R ^a' , S (O) NR ^{c '} R ^d' , S (O) ₂ R ^{a '} , S (O) ₂ NR ^c' R ^{d '} , SR ^b' , C _1-10 alkyl, C _1-10 haloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C _1-10 alkyl , C _1-10 haloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl A compound of formula I optionally substituted by 1, 2 or 3 R ¹⁴ .

In some embodiments, the compound is

Ar is aryl or heteroaryl, optionally substituted by 1, 2, 3, 4 or 5 W-X-Y-Z, respectively;

R ¹ is H;

R ² is H;

R ³ is each C _1-6 alkyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl optionally substituted by 1, 2 or 3 W'-X'-Y'-Z ';

R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each H compounds.

In many places herein, substituents of compounds of the invention are described in groups or in ranges. Specifically, all respective individual subcombinations belonging to this group and range are also included in the present invention. For example, the term “C _1-6 alkyl” is specifically used to individually disclose methyl, ethyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl and C ₆ alkyl.

In addition, certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in one embodiment. Conversely, many features of the invention, which are, for brevity, described in the context of one aspect, may be provided individually or by any suitable subcombination.

The term "n-membered", where n is an integer, typically refers to the number of ring-forming atoms in the residue, where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.

As used herein, the term "alkyl" refers to a straight or branched saturated hydrocarbon group. Examples of alkyl groups include methyl (Me), ethyl (Et), propyl (e.g. n-propyl and isopropyl), butyl (e.g. n-butyl, isobutyl, t-butyl), pentyl (e.g. n-pentyl , Isopentyl, neopentyl) and the like. Alkyl groups may contain 1 to about 20, 2 to about 20, 1 to about 10, 1 to about 8, 1 to about 6, 1 to about 4, or 1 to about 3 carbon atoms. have. The term "alkylenyl" refers to a divalent alkyl linking group.

As used herein, "alkenyl" refers to an alkyl group having one or more double carbon-carbon bonds. Examples of alkenyl groups include ethenyl, propenyl, cyclohexenyl and the like. The term "alkenylenyl" refers to a divalent alkenyl linking group.

As used herein, "alkynyl" refers to an alkyl group having one or more triple carbon-carbon bonds. Examples of alkynyl groups include ethynyl, propynyl, and the like. The term "alkynylenyl" refers to a divalent alkynyl linking group.

As used herein, "haloalkyl" refers to an alkyl group having one or more halogen substituents. Examples of haloalkyl groups include CF, CF ₃ , C ₂ F ₅ , CHF ₂ , CCl ₃ , CHCl ₂ , C ₂ Cl _5, and the like.

As used herein, “aryl” refers to monocyclic or polycyclic (eg, 2, 3 or 4) such as, for example, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like. Having a fused ring) means an aromatic hydrocarbon. In some embodiments, an aryl group has 6 to about 20 carbon atoms.

As used herein, "cycloalkyl" refers to a non-aromatic cyclic hydrocarbon comprising a ring-closed alkyl, alkenyl and alkynyl group. Cycloalkyl groups can include mono- or polycyclic (eg, having two, three or four fused rings) ring systems and spiro ring systems. Ring-forming carbon atoms of cycloalkyl groups may be optionally substituted by oxo or sulfido. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norfinyl, norcanyl, Adamantyl and the like. The definition of cycloalkyl also includes residues having at least one aromatic ring fused to the cycloalkyl ring (ie, having a common bond), for example benzo, pyrido or thieno derivatives such as pentane, pentene, hexane, etc. do.

As used herein, "heteroaryl" group refers to an aromatic heterocycle having at least one heteroatom ring element such as sulfur, oxygen or nitrogen. Heteroaryl groups include monocyclic and polycyclic (eg, having two, three or four fused rings) systems. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyryl, Oxazolyl, benzofuryl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, furinyl , Carbazolyl, benzimidazolyl, indolinyl, and the like. In some embodiments, the heteroaryl group has 1 to about 20 carbon atoms and in further embodiments has about 3 to about 20 carbon atoms. In some embodiments, the heteroaryl group contains 3 to about 14, 3 to about 7, or 5 to 6 ring forming atoms. In some embodiments, the heteroaryl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms.

As used herein, "heterocycloalkyl" refers to a non-aromatic heterocycle including closed ring alkyl, alkenyl and alkynyl groups in which one or more ring-forming carbon atoms is replaced by a heteroatom such as an O, N or S atom. do. Heterocycloalkyl groups can be monocyclic or polycyclic (eg, both fused and spiro systems). Examples of "heterocycloalkyl" groups include morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxol, benzo -1,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl and the like. Ring-forming carbon atoms and heteroatoms of heterocycloalkyl groups may be optionally substituted by oxo or sulfido. In addition, the definition of heterocycloalkyl includes residues having one or more aromatic rings (ie, having one bond in combination) fused to a non-aromatic heterocyclic ring, such as phthalimidyl, naphthalimidyl and hetero Benzo derivatives of the cycle, such as indolene and isoindolene groups. In some embodiments, the heterocycloalkyl group has 1 to about 20 carbon atoms and in further embodiments has about 3 to about 20 carbon atoms. In some embodiments, the heterocycloalkyl group contains 3 to about 14, 3 to about 7 or 5 to 6 ring-forming atoms. In some embodiments, the heterocycloalkyl group has 1 to about 4, 1 to about 3 or 1 to 2 heteroatoms. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 triple bonds.

As used herein, "halo" or "halogen" includes fluoro, chloro, bromo and iodo.

As used herein, "alkoxy" refers to an -O-alkyl group. Examples of alkoxy groups include methoxy, ethoxy, propoxy (eg n-propoxy and isopropoxy), t-butoxy and the like.

As used herein, "haloalkoxy" refers to an -O-haloalkyl group. An example of a haloalkoxy group is OCF ₃ .

As used herein, "arylalkyl" refers to alkyl substituted by aryl and "cycloalkylalkyl" refers to alkyl substituted by cycloalkyl. An example of an arylalkyl group is benzyl.

As used herein, "heteroarylalkyl" refers to an alkyl group substituted by a heteroaryl group.

As used herein, "amino" refers to NH ₂ .

As used herein, "alkylamino" refers to an amino group substituted by an alkyl group.

As used herein, "dialkylamino" refers to an amino group substituted by two alkyl groups.

As used herein, "dialkylaminocarbonyl" refers to an alkyloxy (alkoxy) group substituted by a dialkylamino group.

As used herein, "cycloalkylcarbonyl (alkyl) amino" means an alkylamino group substituted by a carbonyl group (on the N atom of the alkylamino group) and this carbonyl group is substituted by a cycloalkyl group. The term "cycloalkylcarbonylamino" refers to an amino group substituted by a carbonyl group (on the N atom of the amino group) and the carbonyl group substituted by a cycloalkyl group. The term "cycloalkylalkylcarbonylamino" refers to an amino group substituted by a carbonyl group (on the N atom of the amino group) and the carbonyl group substituted by a cycloalkylalkyl group.

As used herein, "alkoxycarbonyl (alkyl) amino" means an alkylamino group substituted by an alkoxycarbonyl group on the N atom of the alkylamino group. The term "alkoxycarbonylamino" refers to an amino group substituted by an alkoxycarbonyl group on the N atom of an amino group.

As used herein, "alkoxycarbonyl" refers to a carbonyl group substituted by an alkoxy group.

As used herein, "alkylsulfonyl" refers to a sulfonyl group substituted by an alkyl group. The term "alkylsulfonylamino" refers to an amino group substituted by an alkylsulfonyl group.

As used herein, "arylsulfonyl" refers to a sulfonyl group substituted by an aryl group.

As used herein, "dialkylaminosulfonyl" refers to a sulfonyl group substituted by dialkylamino.

As used herein, "arylalkyloxy" means O-arylalkyl. An example of an arylalkyloxy group is benzyloxy.

As used herein, "cycloalkyloxy" means O-cycloalkyl. An example of a cycloalkyloxy group is cyclophenyloxyl.

As used herein, “heterocycloalkyloxy” means O-heterocycloalkyl.

As used herein, “heteroaryloxy” means O-heteroaryl. An example is pyridyloxy.

As used herein, "acylamino" refers to an amino group substituted by an alkylcarbonyl (acyl) group. The term "acyl (alkyl) amino" refers to an alkyl group substituted by an alkylcarbonyl (acyl) group and an alkyl group.

 As used herein, "alkylcarbonyl" refers to a carbonyl group substituted by an alkyl group.

 As used herein, "cycloalkylaminocarbonyl" refers to a carbonyl group substituted by an amino group, which amino group is substituted by a cycloalkyl group.

As used herein, "aminocarbonyl" refers to a carbonyl group substituted with an amino group (ie, CONH ₂ ).

As used herein, "hydroxyalkyl" refers to an alkyl group substituted by a hydroxyl group. An example is CH ₂ OH.

 As used herein, "alkylcarbonyloxy" refers to an oxy group substituted by a carbonyl group, which carbonyl group is substituted by an alkyl group.

[여기서, R은 H가 아닌 임의의 잔기이다]를 갖는 잔기를 의미한다.As used herein, "N-substituted piperidin-3-yl" is represented by the formula:

A moiety having the term "where R is any residue other than H".

[여기서, R은 H가 아닌 임의의 잔기이다]를 갖는 잔기를 의미한다. 일반적으로, "치환된" 또는 "치환"이란 용어는 수소가 수소 이외의 치환체로 대체되는 것을 의미힌다. As used herein, "4-substituted piperazin-1-yl" is represented by the formula

A moiety having the term "where R is any residue other than H". In general, the term "substituted" or "substituted" means that hydrogen is replaced with a substituent other than hydrogen.

The compounds described herein may be asymmetric (eg, may have one or more stereogenic centers). Unless otherwise stated, all stereoisomers such as enantiomers and diastereomers are also included in the present invention. Compounds of the invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Processes for preparing in optically active forms from optically active starting materials, for example the resolution or stereoselective synthesis of racemic mixtures, are known in the art. Many geometric isomers, such as olefins, C═N double bonds, and the like, may also be present in the compounds described herein, and all such stable isomers are included in the present invention. Cis and trans geometric isomers of the compounds of the invention are described and may be isolated as a mixture of isomers or as separate isomeric forms.

Decomposition of the racemic mixture of compounds can be carried out by any of a number of methods known in the art. One example of such a method involves fractional recrystallization using an optically active salt-forming organic acid, “chiral decomposition acid”. Suitable dissolution reagents for fractional recrystallization are, for example, D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or various optical acids such as β-camphorsulfonic acid. Active camphorsulfonic acid. Other degradation reagents suitable for fractional recrystallization are α-methylbenzylamine in pure stereoisomeric form (e.g., S and R forms, or pure diastereomeric forms), 2-phenylglycinol, noephedrine, ephedrine, N-methyl Ephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

Degradation of the racemic mixture may be performed by elution using a column packed with optically active separation reagents such as dinitrobenzoylphenylglycine. Suitable elution solvent compositions can be determined by one skilled in the art.

Compounds of the invention also include tautomeric forms, such as keto-enol tautomers.

Compounds of the present invention may also include all isotopes of atoms present in intermediates or final compounds. Isotopes include atoms with the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

The phrase “pharmaceutically acceptable” means a compound, substance, that is suitable for use in contact with tissues of humans and animals at a reasonable benefit / hazardous rate without undue toxicity, irritation, allergic reactions or other problems or complications within the scope of good medical judgment. , Compositions and / or dosage forms.

The invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, the term "pharmaceutically acceptable salts" refers to derivatives in which the parent compound is modified by converting an acid or basic moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; Alkali or organic salts of acidic residues such as carboxylic acids and the like. Pharmaceutically acceptable salts of the present invention include conventional non-toxic salts or quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of the invention can be synthesized using conventional chemical methods from the parent compound comprising a basic or acidic moiety. Generally, such salts can be prepared by reacting the free acid or base form of such a compound with stoichiometric amounts of a suitable base or acid in water or an organic solvent or in a mixture of two organic solvents, generally ether, ethyl Preference is given to non-aqueous media such as acetate, ethanol, isopropanol or acetonitrile. A list of suitable salts is described in the literature, which is hereby incorporated by reference in its entirety. Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977).

The invention also includes prodrugs of the compounds described herein. As used herein, the term “prodrug” refers to any covalently bonded carrier that releases the active parent drug when administered to a mammalian subject. Prodrugs can be prepared by modifying functional groups present in a compound, either by conventional treatment, or by modifying the parent compound in vivo. Prodrugs are compounds in which a hydroxyl, amino, sulfidyl or carboxyl group is bound to any group of compounds and, when administered to a mammalian subject, degrades to form free hydroxyl, amino, sulfidyl or carboxyl groups, respectively. Include. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention. The preparation and use of prodrugs is described in the literature, see T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entirety.

synthesis

The novel compounds of the present invention can be prepared by a variety of methods known to those skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the following methods in combination with methods known in the art of synthesis of synthetic organic chemistry or modifications thereof that are apparent to those skilled in the art.

The compounds of the present invention can be prepared from readily available starting materials using the following general methods and processes. It will be appreciated that typical or preferred process conditions (ie, reaction temperature, time, molar ratio of reactants, solvents, pressures, etc.) are used but other process conditions may be used, unless otherwise noted. Optimum reaction conditions may vary depending on the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by conventional optimization processes.

The process described herein can be monitored by any suitable method known in the art. For example, product formation can be performed using nuclear magnetic resonance spectroscopy (e.g., ¹ H or ¹³ C), infrared spectroscopy, spectroscopy (e.g. UV-visible line), or spectroscopic means such as mass spectrometry, or high performance liquid chromatography (HPLC). Or by chromatography, such as thin layer chromatography.

Preparation of compounds may involve the protection and deprotection of various chemical groups. The need for protection and deprotection and the selection of suitable protection groups can be readily determined by one skilled in the art. The chemistry of a protecting group can be found in the literature cited herein by reference in its entirety. Greene, et al., Protective Groups in Organic Synthesis, 2d. Ed., Wiley & Sons, 1991].

The reaction of the methods described herein can be carried out in a suitable solvent, which can be readily selected by one skilled in the art of organic synthesis. Suitable solvents may be substantially unreactive at the temperature at which the reaction is carried out with the starting materials (reactants), intermediates or products. That is, the temperature may range from the cooling temperature of the solvent to the boiling point of the solvent. A given reaction can be carried out in one solvent or a mixture of one or more solvents. Depending on the specific reaction step, a suitable solvent for the particular reaction step can be selected.

The compound of the present invention can be produced, for example, using the following reaction routes and methods.

A series of N- (piperidin-3-yl) carboxamides of Formula 4 can be prepared by the method outlined in Scheme 1. Coupling the 1- (tert-butoxycarbonyl) piperidine-3-carboxylic acid (1) with acid chloride R ³ COCl in the presence of a Hunig base or potassium carbonate to give the desired product (2). can do. The Boc protecting group (2) can be removed by treatment with HCl in 1,4-dioxane to give the amino salt (3), which can be directly coupled with the appropriate chloride ArLCl to give the final compound of formula (4). Alternatively, the urea of formula 4 'can be prepared via activated p-nitro-carbamate (3') or by reacting piperidine (3) with an appropriate isocyanate.

Alternatively, the same series of N- (piperidin-3-yl) carboxamides of Formula 4 can be prepared in a manner similar to that described above except for the coupling sequence, as shown in Scheme 2.

Alternatively, the same series of N- (piperidin-3-yl) carboxamides of Formula 4 can be prepared by the method outlined in Scheme 3. The 3-amino-piperidine derivative (5) is coupled to the carboxylic acid using a coupling reagent such as BOP in a suitable solvent such as DMF in the presence of a suitable base, such as N-methylmorpholine, according to Scheme 3 The final product 4 can be obtained.

A series of N- (piperidin-3-yl) carboxamides of Formula 6 can be prepared by the method outlined in Scheme 4. Compound (5) was coupled to N-Boc-piperidinyl carboxylic acid (7) using a coupling reagent such as BOP in the presence of a suitable base such as N-methylmorpholine to give an amido compound of formula (8). Can be. The amine compound of formula 9 can be obtained by removing the Boc group of compound (8) by treatment with HCl in 1,4-dioxane. The amine compound of formula 9 can be coupled with compound RX to give the desired product of formula 6, wherein X is a leaving group such as halide, and RX is sulfonyl chloride, acid chloride, alkyl chloroformate or alkyl bromide Can be).

A series of 5-substituted 3-aminopiperidine of Formula 10 can be prepared by the method outlined in Scheme 5. L-glutamic acid dimethyl ester (11) is Boc-protected with di-tert-butyl dicarbonate to afford N-Boc compound (12). Compound (12) is reacted with compound RX (e.g. alkyl bromide or alkyl iodide) in a suitable solvent such as DMF or THF in the presence of a suitable base such as sodium hydride, LDA or LiHMDS to provide 4-alkyl dimethyl ester (13) To prepare. The ester group is reduced with a suitable reducing agent such as NaBH ₄ / CaCl ₂ to afford di-OH compound 14. Compound 15 can be obtained by reacting the hydroxyl group of compound 14 with MsCl under basic conditions to a better leaving group such as OMs. The desired 5-substituted 3-aminopiperidine 10 can be prepared by reacting compound 15 with benzylamine, followed by palladium catalytic hydrogenation.

A series of spiro-3-aminopiperidine of Formula 17 can be prepared by a similar method as set forth in Scheme 6, where r can be 1-5. The diester compound 12 may be reacted with a dihalide compound such as a dibromoalkyl compound in the presence of a suitable base such as LiHMDS in a suitable solvent such as THF to obtain a cycloalkyl compound 18. The ester group of compound (18) can be reduced in a suitable solvent such as EtOH / THF with a suitable reducing reagent such as a combination of NaBH ₄ / CaCl ₂ to afford di-OH compound (19). Spiro compound 17 can be obtained from compound 19 using a process similar to the process outlined in Scheme 5.

A series of 3-substituted-3-aminopiperidine of Formula 22 can be prepared according to the methods outlined in Scheme 7 wherein R can be alkyl, aryl, arylalkyl, cycloalkyl or cycloalkylalkyl. have. The ketone compound 23 can be treated with TsNH ₂ to afford the imino compound 24. Compound 24 is then reacted with a Grignard reagent such as RMgBr to give Ts-protected-amine compound 25. The Ts group of compound (25) can be removed using PhSH to afford compound (26). The amino group is then protected with a Boc group using (Boc) ₂ O in the presence of a suitable base such as triethylamine to prepare a Boc-protected compound (27). The Bn group of compound (27) is removed by hydrogenation with palladium as catalyst to give the desired ferridine compound (22).

Tertiary amides of Formula 28 may be prepared as shown in Scheme 8. Reductive amination of 3-aminopiperidine (5) with a suitable aldehyde (R 'is, for example, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, etc.) to give secondary amines (29) Is obtained and coupled to a suitable acid using a BOP reagent or any other suitable coupling agent to give the desired amide 28.

Alternatively, the same series of N- (piperidin-3-yl) carboxamides of Formula 30 can be prepared by the method outlined in Scheme 9, wherein X is a leaving group such as halo. The alkyl group R ² can be introduced directly into the N-atom of the amide 4 to form the desired amide 3 using a suitable catalyst such as tributylammonium bromide under the conditions of the phase transfer catalyst. .

A series of carboxamides of Formula 31, wherein A is S, O, CH ₂ or NR, where R is alkyl, cycloalkyl, arylalkyl, etc., is represented by Scheme 10, wherein R is alkyl, aryl, arylalkyl And X is a leaving group such as halo). Ester compound (32) is treated with excess alkyl bromide or iodide in a suitable solvent such as DMF or THF in the presence of a suitable base such as sodium hydride or LDA to obtain an R-substituted ester (33), which is a basic valence Decomposition yields the carboxylic acid 34. The carboxylic acid 34 is coupled to 3-aminopiperidine 5 to afford the desired product 31.

A series of carboxylic acids of formula 38, wherein X is S or O, is represented by Scheme 11, wherein R may be alkyl or arylalkyl, and Cy may be aryl, heteroaryl, cycloalkyl or heterocycloalkyl It may be prepared according to the method outlined in A suitable thiol or alcohol 35 is reacted with methyl bromoacetate in a suitable solvent such as tetrahydrofuran, acetonitrile or dichloromethane in the presence of a suitable base such as potassium carbonate, sodium carbonate, triethylamine or sodium hydride to thioether Or ether compound 36 is obtained. Compound (36) is treated with excess alkyl bromide or iodide in a suitable solvent such as DMF or THF in the presence of a suitable base such as sodium hydride or LDA to give a substituted ester compound (37), which is subjected to basic hydrolysis. To obtain the desired carboxylic acid (38).

As shown in Scheme 12, ether or thioether 36 is prepared in the presence of a suitable base such as NaH, LDA or LiHMDS in an equivalent solvent of 1 equivalent of an appropriate alkyl bromide or iodide R'Br ( Alkylation with I) followed by secondary alkylation with R ^" Br (I) in a suitable solvent such as DMSO in the presence of a suitable base such as NaH to give the ester compound (39), which is subjected to basic hydrolysis to give the desired carboxylic acid ( Calculate 40).

Alternatively, a series of carboxylic acids of Formula 44 can be prepared starting from a suitable cyclic ketone or thioketone 41 according to Scheme 13, wherein the rings in compound 44 can be non-aromatic, aromatic or heteroaromatic. have).

A series of carboxylic acids of formula 49, wherein X is O or S, can be prepared according to the method outlined in Scheme 14. Compound 45 is O- or S-alkylated with a suitable alkyl chloride or alkyl bromide to give methyl ester 46. Compound 46 is alkylated with alkyl bromide or iodide in a suitable solvent such as THF in the presence of a suitable base such as appropriate LDA to yield methyl ester 47, which is a suitable solvent such as DMSO in the presence of a base such as NaH. Second alkylation corresponding esters 48 with other alkyl bromide or iodide can be prepared. Finally, ester 48 is subjected to basic hydrolysis to yield the desired carboxylic acid 49.

Alternatively, a series of carboxylic acids of formula 53, wherein X is O or S and u is 1 or 2, can be prepared according to Scheme 15. A nitrile 51 is prepared by reacting a suitable alcohol or thiol 50 with chloroacetonitrile under suitable conditions such as reflux in the presence of a base such as sodium ethoxide. Alkylation of compound (51) in the standard manner shown in Scheme 15 yields nitrile (52), which is subjected to basic hydrolysis to yield the desired carboxylic acid (53), wherein Cy is aryl, heteroaryl, cycloalkyl or heterocycloalkyl. And the like).

Alternatively, carboxylic acid 59, wherein Cy may be aryl, heteroaryl, cycloalkyl or heterocycloalkyl, zinc trifluoromethanesulfonate with the appropriate alcohol CyCH ₂ OH and thioglycolic acid 54 It can be prepared by reacting under the same conditions as reflux in the presence of Lewis acid such as to prepare the acid compound (55). Compound 55 can then be processed in the manner shown in Scheme 16 to yield the desired carboxylic acid 59.

According to Scheme 17, the thioether compound 6 can be oxidized to the corresponding sulfone 61 using a suitable oxidizing agent such as 3-chloroperoxybenzoic acid. According to Scheme 17, as already described, a series of carboxylic acids of formula 63 can be prepared. The same sequence (conversion of thioether to sulfone) can be used in any of the schemes described above.

A series of carboxylic acids of formula 68 can be prepared by the method outlined in Scheme 18. N-Boc glycine methyl ester (64) was prepared in the same manner as described above _. Alkylation may yield alkylated compound 65. The Boc group is removed with TFA and then N-alkylated with an appropriate alkyl bromide or iodide CyCH ₂ Br (or I) to induce the formation of ester (67), which is subjected to basic hydrolysis to give the desired carboxylic acid (68). can do.

Alternatively, according to Scheme 19, the same series of carboxylic acids of Formula 68 are prepared as described above except that under appropriate conditions, compound 67 is prepared using the corresponding aldehyde CyCHO and compound 66 with reductive amination. It can be prepared in a similar manner to the above.

A series of carboxylic acids of formula 72 can be prepared according to the method outlined in Scheme 20. Cbz-protected amine 69 is reacted with 2-bromo methyl acetate to give methyl ester 70. Alkylation in the manner as set out below yields a dialkylated methyl ester (71). Subsequently, basic hydrolysis of the ester (71) yields the desired carboxylic acid (72). The Cbz group of compound 72 may be removed in a later step under hydrolysis conditions.

A series of amido compounds of formula 76 can be prepared according to the methods outlined in Scheme 21. Tert-butyl piperidin-3-ylcarbamate (69) is an aryl halide or heteroaryl halide ArX such as bromobenzene in the presence of a base such as tert-butoxide in a solvent such as dimethyl sulfoxide, wherein Ar may be optionally substituted by one or more substituents such as halo or alkyl) to yield compound 74. The Boc protecting group of compound 74 can be removed with HCl in 1,4-dioxane to afford the amine compound 75 as an HCl salt. Amine compound (75) in a suitable solvent such as DMF in the presence of a suitable base such as 4-methylmorpholine and suitable coupling such as benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate Coupling with a suitable carboxylic acid R ³ COOH in the presence of a reagent may yield the final amido compound of formula 76.

Way

Compounds of the invention can modulate the activity of 11βHSD1 and / or MR. The term "modulate" means the ability to increase or decrease the activity of an enzyme or receptor. Accordingly, the compounds of the present invention can be used in a method of modulating 11βHSD1 and / or MR by contacting an enzyme or receptor with one or more compounds or compositions described herein. In some embodiments, the compounds of the present invention may act as inhibitors of 11βHSD1 and / or MR. In a further aspect, the compounds of the present invention can be used to modulate the activity of 11-β-HSD1 and / or MR by administering to the subject in need of control of an enzyme or receptor, a controlled amount of a compound of the invention.

The present invention further provides a method of inhibiting the conversion of cortisone to cortisol in a cell or a method of inhibiting the production of cortisol in a cell, wherein the conversion or production of cortisol at least partially mediates 11βHSD1 activity. Methods of determining the level of conversion from cortisone to cortisol and vice versa, as well as methods of measuring levels of intracellular cortisone and cortisol, are common in the art.

The invention further provides a method of increasing the insulin sensitivity of a cell by contacting the cell with a compound of the invention. Insulin sensitivity measurement methods are common in the art.

The invention further encompasses aberrant activity and overexpression of 11βHSD1 and / or MR in a subject (eg, a patient) by administering to the subject in need thereof a therapeutically effective amount or dosage of a compound of the invention or a pharmaceutical composition thereof. It provides a method for treating a disease associated with activity or expression. Examples of diseases may include diseases, diseases or conditions that are directly or indirectly related to the expression or activity of an enzyme or receptor. 11βHSD1-associated diseases may also include diseases, diseases or conditions that can be prevented, ameliorated or treated by modulating enzyme activity.

Examples of 11βHSD1-related diseases include obesity, diabetes, glucose intolerance, insulin resistance, hyperglycemia, hypertension, hyperlipidemia, cognitive impairment, dementia, glaucoma, cardiovascular disease, osteoporosis and inflammation. Further examples of 11βHSD1-related diseases include metabolic syndrome, type 2 diabetes, androgen excess (hirsutism, dysmenorrhea, hyperandrogenosis) and polycystic ovary syndrome (PCOS).

The invention further provides a method of modulating MR activity by contacting MR with a compound of the invention, a pharmaceutically acceptable salt, prodrug or composition thereof. In some embodiments, the regulation can be inhibition. In a further aspect, methods are provided for inhibiting binding of aldosterone to MR (optionally intracellular). Methods of measuring MR activity and measuring inhibition of aldosterone binding are common in the art.

The invention further provides a method of treating a disease related to the activity or expression of MR. Examples of diseases related to the activity or expression of MR include hypertension, as well as cardiovascular, renal, and inflammatory pathologies such as heart failure, atherosclerosis, atherosclerosis, coronary artery disease, thrombosis, angina, peripheral vascular disease, vascular wall Injury, stroke, dyslipidemia, hyperlipoproteinemia, diabetic dyslipidemia, mixed dyslipidemia, hypercholesterolemia, hypertriglyceridemia, and type 1 diabetes, type 2 diabetes, obesity metabolic syndrome, insulin resistance and general Diseases associated with aldosterone-related target organ damage.

As used herein, the term "cell" refers to a cell that is in vitro, ex vivo or in vivo. In some embodiments, the ex vivo cell may be part of a tissue sample incised from an organism, eg, a mammal. In some embodiments, the cells in vitro can be cells in cell culture. In some embodiments, the cells in vivo are living cells in an organism such as a mammal. In some embodiments, the cell is a cell comprising adipocytes, pancreatic cells, hepatocytes, nerve cells or eye.

As used herein, the term "contacting" means to bring together the residues described in an in vitro or in vivo system. For example, "contacting" the 11βHSD1 enzyme with a compound of the present invention not only administers the compound of the present invention to an individual or patient having 11βHSD1, eg, a human, but also, for example, a compound of the present invention. Incorporating into a sample containing a cellular or purified agent containing 11βHSD1 enzyme.

As used herein, the term "individual" or "patient" is used interchangeably and includes animals including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses or Primates, most preferably humans.

As used herein, the phrase “therapeutically effective amount” refers to an activity that induces a biological or medical response sought by a researcher, veterinarian, physician or other clinician in a tissue, system, animal, subject or human, comprising one or more of the following: The amount of the compound or pharmaceutical agent is:

(1) prevention of disease; For example, the prevention of a disease, condition or disease in a subject who is susceptible to a disease, condition or illness but has not yet experienced or exhibited the pathology or symptom of the disease (non-limiting examples include metabolic syndrome, hypertension, obesity, insulin resistance, Hyperglycemia, hyperlipidemia, type 2 diabetes, hyperandrogenosis (hirsutism, dysmenorrhea, hyperandrogenosis) and polycystic ovary syndrome (PCOS) are prevented);

(2) inhibition of disease; For example, inhibition of a disease, condition or condition (ie, inhibition of further development of the pathology and / or symptoms) in an individual who is experiencing or exhibiting the etiology or condition of the disease, condition or disease, eg metabolic syndrome, Suppression of the development of hypertension, obesity, insulin resistance, hyperglycemia, hyperlipidemia, type 2 diabetes, hyperandrogenosis (hirsutism, dysmenorrhea, hyperandrogenosis) or polycystic ovary syndrome (PCOS), or stabilizing viral load in case of viral infection; And

(3) improvement in disease; For example, amelioration (ie, recovery of etiology and / or symptoms) of a disease, condition or condition in an individual experiencing or exhibiting a disease, condition or pathology or symptom of the disease, for example metabolic syndrome, hypertension, obesity , Reducing the severity of insulin resistance, hyperglycemia, hyperlipidemia, type 2 diabetes, hyperandrogenosis (hirsutism, dysmenorrhea, hyperandrogenosis) and polycystic ovarian syndrome (PCOS), or a decrease in viral load in the case of viral infection.

Pharmaceutical Formulations and Dosage Forms

When used as a medicament, the compound of formula I can be administered in the form of a pharmaceutical composition. These compositions can be prepared by methods well known in the art of pharmacy and can be administered by a variety of routes depending on whether topical or systemic treatment is desired and depending on the area being treated. Administration may be topical (including ocular and mucosal membranes including intranasal, vaginal and rectal delivery), lungs (eg, inhalation or aeration of powders or aerosols including sprays; intratracheal, nasal, epidermal and transdermal), ocular Oral or parenteral administration. Methods for ocular delivery may include topical administration (eye drops), subconjunctival, perocular or intravitreal injection, or insertion of a balloon catheter or ocular insert into the conjunctival sac. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; Or intracranial, eg intrathecal or intraventricular administration. Parenteral administration may be in a single bolus dosage form or may be, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, solutions and powders. Ordinary pharmaceutical carriers, aqueous powder or oily bases, thickeners and the like may be necessary or desirable.

The present invention also includes pharmaceutical compositions containing, as active ingredient, one or more of the compounds of the present invention and one or more pharmaceutically acceptable carriers. In the preparation of the compositions of the present invention the active ingredient is typically mixed with the excipient or diluted with the excipient or packaged in a carrier in the form of a capsule, sachets, paper or other container, for example. If an excipient is used as a diluent, it may be a solid, semisolid or liquid material which acts as an excipient, carrier or medium for the active ingredient. Thus, the compositions may be used in tablets, pills, powders, lozenges, cachets, cachets, elixirs, suspensions, emulsions, solvents, syrups, aerosols (solid or liquid media), for example up to 10% by weight of active compound In the form of ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.

In preparing the composition, the active compound may be ground to a suitable particle size before being combined with the other ingredients. If the active compound is substantially insoluble, it may be ground to a particle size of less than 200 mesh. If the active compound is substantially water soluble, it can be milled by adjusting the particle size to, for example, about 40 mesh to provide a substantially uniform distribution in the composition.

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose , Water, syrup and methyl cellulose. The composition may be a lubricant such as talc, magnesium stearate and mineral oil; Wetting agents; Emulsifying and suspending agents; Preservatives such as methyl- and propylhydroxyl-benzoate; Sweeteners; And flavourants. The compositions of the present invention can be prepared to provide rapid, delayed or delayed release of the active ingredient after administration to a patient using methods known in the art.

The compositions may be formulated in unit dosage forms each dose containing about 5 to about 100 mg, more generally about 10 to about 30 mg of active ingredient. The term "unit dosage form" is a physically discrete unit suitable for unit administration to human subjects and other mammals, each unit being precalculated to provide the desired therapeutic effect with respect to a suitable pharmaceutical excipient. A suitable amount of the active substance is included.

The active compounds can be effective over a wide range of dosages and are generally administered in pharmaceutically effective amounts. However, the amount of compound actually administered can usually be determined according to the relevant circumstances including the condition to be treated by the physician, the route of administration chosen, the actual compound administered, age, weight and individual patient's response, the severity of the patient's symptoms, and the like.

 To prepare a solid composition, such as a tablet, the main active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition comprising a homogeneous mixture of the compounds of the invention. When referring to the preformulation composition as homogeneous, the active ingredient is usually dispersed completely in the composition so that the composition can be easily separated into equal amounts of effective unit dosage forms, such as tablets, pills and capsules. Such solid preformulations are divided into unit dosage forms of the type described above, which comprises, for example, 0.1 to about 500 mg of the active ingredient of the invention.

Tablets or pills of the present invention may be coated or otherwise synthesized to provide dosage forms that provide prolonged action benefits. For example, tablets or pills may include internal and external dosage components, which are in the form of an envelope covering the internal dosage component. The two components can be separated into an enteric layer which inhibits the decomposition of the stomach and allows the internal components to pass through or intact to the duodenum intact. Various materials can be used as such intestinal layers or coatings, and such materials include a plurality of polymer acids and mixtures of polymer acids together with shellac, cetyl alcohol and cellulose acetate.

Liquid forms in which the compounds and compositions of the present invention may be incorporated by oral administration or injection may be used as aqueous solutions, suitable flavor syrups, aqueous or oily suspensions and flavor emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil. As well as elixirs and similar pharmaceutical vehicles.

 Inhalation or aeration compositions include solutions and suspensions, and powders in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof. Liquid or solid compositions may comprise suitable pharmaceutically acceptable excipients as described above. In some embodiments, the composition is administered for local or systemic effects by the oral or nasal breathing route. The composition can be sprayed using an inert gas. The sprayed solution can breathe directly from the spray device, or the spray device can be attached to a face mask tent or an intermittent positive pressure breathing machine. Solutions, suspensions or powder compositions may be administered orally or nasal from devices that deliver the formulation in a suitable manner.

The amount of the compound or composition to be administered to the patient may vary depending on the substance to be administered, the purpose of administration, such as prevention or treatment, the condition of the patient, the method of administration, and the like. In therapeutic applications, the composition may be administered to a patient already suffering from the disease in an amount sufficient to at least partially treat or arrest the symptoms of the disease and its complications. Effective dosages may depend on the judgment of the attending physician, as well as the condition of the disease being treated, depending on factors such as the severity of the disease, the age, weight and general condition of the patient, and the like.

The composition administered to the patient may be in the form of a pharmaceutical composition described above. These compositions may be sterilized by conventional sterilization techniques or may be sterile filtered. The aqueous solution can be packed for use or lyophilized and the lyophilized formulation can be combined with a sterile aqueous carrier prior to administration. The pH of the compound formulation can typically be 3-11, more preferably 5-9, most preferably 7-8. It is understood that the use of certain of the aforementioned excipients, carriers or stabilizers can form pharmaceutical salts.

The therapeutic dosage of a compound of the present invention may vary, for example, depending on the particular method of treatment, the method of administering the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the present invention in a pharmaceutical composition can vary depending on a number of factors, including dosage, chemical properties (eg hydrophobicity), and route of administration. For example, the compounds of the present invention can be prepared in physiological aqueous buffer solution comprising about 0.1 to about 10% w / v of the compound by parenteral administration. Some typical dosage ranges are from about 1 μg / kg body weight to about 1 g / kg body weight per day. In some embodiments, the dosage range is about 0.01 mg / kg body weight to about 100 mg / kg body weight per day. Dosage may depend on such variables as the form and extent of the disease or condition, the general health of the particular patient, the relative biological efficacy of the selected compound, the formulation of the excipient and the route of administration thereof. Effective dosages may be extrapolated from dose-response curves derived from in vitro or animal model test systems.

The compounds of the present invention may also be formulated in combination with one or more additional active ingredients which may include pharmaceutical agents, such as anti-viral agents, antibodies, immunosuppressants, anti-inflammatory agents, and the like.

Labeled Compounds and Assay Methods

Other aspects of the invention are not only useful in radio-imaging, but also useful for localizing and quantifying enzymes in tissue samples, including humans, in vitro and in vivo assays, and for identifying ligands by inhibitory binding of radiolabeled compounds. It relates to radiation-labeled compounds of the invention. Accordingly, the present invention includes enzyme assays comprising such radio-labeled compounds.

The present invention further includes isotope-labeled compounds of the invention. An “isotope” or “radiation-labeled” compound is a compound of the invention, wherein one or more atoms typically have an atomic mass or mass number that is different from the atomic mass or mass number found in nature (ie, naturally occurring). Replaced or substituted by an atom. Suitable radionuclides that can be incorporated into the compounds of the invention include ² H (also described as D as deuterium), ³ H (also described as T as tritium), ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ¹⁸ F, ³⁵ S, ³⁶ Cl, ⁸² Br, ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br, ¹²³ I, ¹²⁴ I, ¹²⁵ I and ¹³¹ I Do not. The radionuclide incorporated into the radiation-labeled compound may depend on the particular application of such radiation-labeled compound. For example, in in vitro receptor labeling and competition assays, compounds incorporating ³ H, ¹⁴ C, ⁸² Br, ¹²⁵ I, ¹³¹ I or ³⁵ S may generally be most useful. For radio-imaging applications, ¹¹ C, ¹⁸ F, ¹²⁵ I, ¹²³ I, ¹²⁴ I, ¹³¹ I, ⁷⁵ Br, ⁷⁶ Br or ⁷⁷ Br may generally be most useful.

A "radiolabeled" or "labeled compound" is understood to be a compound in which one or more radionuclides are incorporated. In some embodiments, the radionuclide is selected from the group consisting of ³ H, ¹⁴ C, ¹²⁵ I, ³⁵ S and ⁸² Br.

Synthetic methods for introducing radio-isotopes into organic compounds apply to the compounds of the present invention and are known in the art.

Radiation-labeled compounds of the invention can be used in screening assays to identify / evaluate compounds. In general aspects, newly synthesized or identified compounds (ie test compounds) can be evaluated for their ability to reduce the binding of the radiation-labeled compounds of the invention to enzymes. Thus, the ability of a test compound to compete for binding to an enzyme with a radiolabeled compound is directly associated with binding affinity.

Kit

The invention also includes a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention, useful for the treatment or prevention of 11βHSD1-associated or MR-related diseases or disorders, obesity, diabetes and other diseases mentioned herein. It includes a pharmaceutical kit containing the above container. Such kits may, in addition, optionally have one or more of various conventional pharmaceutical kit components, such as containers having one or more pharmaceutically acceptable carriers, additional containers, which will be readily appreciated by those skilled in the art. And the like. Instructions such as inserts or labels indicative of the amount of ingredient administered, instructions for administration, and / or instructions for ingredient mixing may be included in the kit.

The invention can be described in more detail by way of specific examples. The following examples are provided for illustrative purposes and are not intended to limit the invention in this way. One skilled in the art can readily recognize various non-essential parameters that are altered or modified to achieve essentially the same results. Compounds in the example portion were found as inhibitors or antagonists of 11-β-HSD1 or MR according to one or more assays provided herein.

Example 1

N- (3R) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-ylcyclohexanecarboxamide

Step 1: N-[(3R) -piperidin-3-yl] cyclohexanecarboxamide hydrochloride

Cyclohexanecarbonyl chloride (70.0 μl, 0.515 mmol) was tert-butyl (3R) -3-aminopiperidine-1-carboxylate (100.0 mg, 0.499 mmol) and carbonic acid in acetonitrile (3.0 mL) at room temperature. To a mixture of potassium (150 mg, 2.1 equiv) was added. The reaction mixture was stirred at rt for 1 h and filtered. The filtrate was concentrated under reduced pressure. The residue was treated with 4.0 M hydrogen chloride in 1,4-dioxane (2.0 mL) for 1 hour at room temperature. The solvent was evaporated under reduced pressure to give the product which was used directly in next step without further purification.

Step 2: N- (3R) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-ylcyclohexane carboxamide

N-[(3R) -piperidin-3-yl] cyclohexanecarboxamide hydrochloride (12.3 mg, 50.0 μmol) in acetonitrile (0.8 mL) was treated with diisopropylethylamine (20.0 μL). To the solution was added 3-chloro-2-methylbenzenesulfonyl chloride (11.3 mg, 50.0 μmol). The resulting mixture was stirred overnight at room temperature and then adjusted to PH = 2.0 using TFA. The mixture was diluted with DMSO (1.0 mL) and purified by preparative HPLC to give the desired product N- (3R) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl-cyclohexane Carboxamide was obtained. LCMS: (M + H) ⁺ = 399.0 / 401.0.

Example 2

N- (3R) -1-[(2-nitrophenyl) sulfonyl] piperidin-3-ylcyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 1. LCMS: (M + H) ⁺ = 396.0.

Example 3

N-[(3R) -1- (2-naphthylsulfonyl) piperidin-3-yl] cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 1. LCMS: (M + H) ⁺ = 401.1.

Example 4

N- (3R) -1-[(3-chlorophenyl) sulfonyl] piperidin-3-ylcyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 1. LCMS: (M + H) ⁺ = 385.1 / 387.1.

Example 5

N- (3R) -1-[(4-propylphenyl) sulfonyl] piperidin-3-ylcyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 1. LCMS: (M + H) ⁺ = 393.1.

Example 6

N-{(3R) -1-[(4-fluorophenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 1. LCMS: (M + H) ⁺ = 369.1.

Example 7

N-{(3R) -1-[(3-methoxyphenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 1. LCMS: (M + H) ⁺ = 381.1.

Example 8

N- (3R) -1-[(3-chloro-4-fluorophenyl) sulfonyl] piperidin-3-ylcyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 1. LCMS: (M + H) ⁺ = 403.0 / 405.0.

Example 9

1- (4-chlorophenyl) -N-[(3R) -1- (phenylsulfonyl) piperidin-3-yl] cyclohexanecarboxamide

Step 1: tert-butyl (3R) -3-([1- (4-chlorophenyl) cyclohexyl] carbonylamino) piperidine-1-carboxylate

1- (4-chlorophenyl) cyclohexanecarboxylic acid (24.6 mg, 103 μmol) and tert-butyl (3R) -3-aminopiperidine-1-carboxylate in N, N-dimethylformamide (1.00 mL) To a mixture of 20.0 mg, 99.7 μmol) was added benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (44.2 mg, 99.9 μmol) followed by 4-methylmorpholine (50.0 μL). . The mixture was stirred at rt overnight. The mixture was diluted with ethyl acetate (5 mL) and washed with NaHCO ₃ (7.5%, 3 × 1 mL) and brine (1 mL). The organic layer was dried over Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to give the product, which was used directly in the next step without further purification.

Step 2: 1- (4-chlorophenyl) -N-[(3R) -piperidin-3-yl] cyclohexanecarboxamide hydrochloride

Tert-butyl (3R) -3-([1- (4-chlorophenyl) cyclohexyl] carbonylamino) -piperidine-1-carboxylate was dissolved in 1,4-dioxane (0.5 for 1 hour at room temperature). mL) in 4.0M hydrogen chloride. The solvent was evaporated to give the corresponding product which was used directly in next step without further purification.

Step 3: 1- (4-chlorophenyl) -N-[(3R) -1- (phenylsulfonyl) piperidin-3-yl] cyclohexanecarboxamide

1- (4-Chlorophenyl) -N-[(3R) -piperidin-3-yl] -cyclohexanecarboxamide hydrochloride (50 μmol) in acetonitrile (1.0 mL) was diluted to N, N-di at room temperature. Treated with isopropylethylamine (20.0 μl), then benzenesulfonyl chloride (9.27 mg, 52.5 μmol) was added. The reaction mixture was stirred at rt overnight, diluted with DMSO (0.8 mL) and adjusted to pH = 2.0. The resulting solution was purified by preparative HPLC to give the corresponding desired product 1- (4-chlorophenyl) -N-[(3R) -1- (phenylsulfonyl) piperidin-3-yl] cyclohexanecarboxamide Obtained. LCMS: (M + H) ⁺ = 461.1 / 463.1.

Example 10

1-methyl-N-[(3R) -1- (phenylsulfonyl) piperidin-3-yl] cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 9. LCMS: (M + H) ⁺ = 365.2.

Example 11

4-hydroxy-N-[(3R) -1- (phenylsulfonyl) piperidin-3-yl] cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 9. LCMS: (M + H) ⁺ = 367.0.

Example 12

4-methoxy-N-[(3R) -1- (phenylsulfonyl) piperidin-3-yl] cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 9. LCMS: (M + H) ⁺ = 381.0.

Example 13

N-[(3S) -1- (phenylsulfonyl) piperidin-3-yl] cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 1. LCMS: (M + H) ⁺ = 351.1.

Example 14

N-{(3S) -1-[(2-fluorophenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 1. LCMS: (M + H) ⁺ = 369.1.

Example 15

N-{(3S) -1-[(2-chlorophenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 1. LCMS: (M + H) ⁺ = 385.1 / 387.1.

Example 16

N-{(3S) -1-[(2-bromophenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 1. LCMS: (M + H) ⁺ = 429.0 / 431.0.

Example 17

N-{(3S) -1-[(2-cyanophenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 1. LCMS: (M + H) ⁺ = 376.1.

Example 18

N-{(3S) -1-[(2-nitrophenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 1. LCMS: (M + H) ⁺ = 396.1.

Example 19

N-{(3S) -1-[(2-methylphenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 1. LCMS: (M + H) ⁺ = 365.1.

Example 20

N-((3S) -1-{[2- (trifluoromethyl) phenyl] sulfonyl} piperidin-3-yl) cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 1. LCMS: (M + H) ⁺ = 419.1.

Example 21

N-((3S) -1-{[2- (trifluoromethoxy) phenyl] sulfonyl} piperidin-3-yl) cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 1. LCMS: (M + H) ⁺ = 435.1.

Example 22

N-{(3S) -1-[(2-phenoxyphenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 1. LCMS: (M + H) ⁺ = 443.1.

Example 23

N-{(3S) -1-[(3-chlorophenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 1. LCMS: (M + H) ⁺ = 385.1 / 387.0.

Example 24

N-{(3S) -1-[(3-cyanophenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 1. LCMS: (M + H) ⁺ = 376.1.

Example 25

N-{(3S) -1-[(3-methylphenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 1. LCMS: (M + H) ⁺ = 365.1.

Example 26

N-((3S) -1-{[3- (trifluoromethyl) phenyl] sulfonyl} piperidin-3-yl) cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 1. LCMS: (M + H) ⁺ = 419.1.

Example 27

N-{(3S) -1-[(3-phenoxyphenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 1. LCMS: (M + H) ⁺ = 443.1.

Example 28

N-{(3S) -1-[(4-fluorophenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 1. LCMS: (M + H) ⁺ = 369.1.

Example 29

N-{(3S) -1-[(4-chlorophenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 1. LCMS: (M + H) ⁺ = 385.1 / 387.1.

Example 30

N-{(3S) -1-[(4-methoxyphenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 1. LCMS: (M + H) ⁺ = 381.1.

Example 31

N-((3S) -1-{[4- (trifluoromethoxy) phenyl] sulfonyl} piperidin-3-yl) -cyclohexane-carboxamide

This compound was prepared using a process similar to the process of Example 1. LCMS: (M + H) ⁺ = 435.1.

Example 32

N- (3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-ylcyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 1. LCMS: (M + H) ⁺ = 399.1 / 401.1.

Example 33

N-((3S) -1-{[4- (acetylamino) phenyl] sulfonyl} piperidin-3-yl) cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 1. LCMS: (M + H) ⁺ = 408.1.

Example 34

N-{(3S) -1-[(4-isopropylphenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 1. LCMS: (M + H) ⁺ = 393.2.

Example 35

N-{(3S) -1-[(4-methylphenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 1. LCMS: (M + H) ⁺ = 365.1.

Example 36

N-((3S) -1-{[4- (methylsulfonyl) phenyl] sulfonyl} piperidin-3-yl) cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 1. LCMS: (M + H) ⁺ = 429.1.

Example 37

N-((3S) -1-{[4- (pyridin-4-yloxy) phenyl] sulfonyl} piperidin-3-yl) cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 1. LCMS: (M + H) ⁺ = 444.1.

Example 38

N-((3S) -1-{[4- (pyridin-3-yloxy) phenyl] sulfonyl} piperidin-3-yl) cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 1. LCMS: (M + H) ⁺ = 444.1.

Example 39

N-{(3S) -1-[(4-tert-butylphenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 1. LCMS: (M + H) ⁺ = 407.2.

Example 40

N-{(3S) -1-[(4-fluoro-2-methylphenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 1. LCMS: (M + H) ⁺ = 383.1.

Example 41

N-{(3S) -1-[(2,3-dichlorophenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 1. LCMS: (M + H) ⁺ = 419.0 / 421.0.

Example 42

N-{(3S) -1-[(2,6-dichlorophenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 1. LCMS: (M + H) ⁺ = 419.0 / 421.1.

Example 43

N-{(3S) -1-[(2,5-dichlorophenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 1. LCMS: (M + H) ⁺ = 419.1 / 421.0.

Example 44

N-{(3S) -1-[(3,4-dichlorophenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 1. LCMS: (M + H) ⁺ = 419.0 / 421.0.

Example 45

N-{(3S) -1-[(3-chloro-4-fluorophenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 1. LCMS: (M + H) ⁺ = 403.1 / 405.1.

Example 46

N-{(3S) -1-[(5-chloro-2-fluorophenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 1. LCMS: (M + H) ⁺ = 403.1 / 405.1.

Example 47

N-{(3S) -1-[(3-chloro-2-fluorophenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 1. LCMS: (M + H) ⁺ = 403.0 / 405.1.

Example 48

N-{(3S) -1-[(2,6-difluorophenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 1. LCMS: (M + H) ⁺ = 387.1.

Example 49

N-{(3S) -1-[(3,4-dimethoxyphenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 1. LCMS: (M + H) ⁺ = 411.1.

Example 50

N-{(3S) -1-[(2,5-dimethoxyphenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 1. LCMS: (M + H) ⁺ = 411.1.

Example 51

N-[(3S) -1- (1-naphthylsulfonyl) piperidin-3-yl] cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 1. LCMS: (M + H) ⁺ = 401.1.

Example 52

N-[(3S) -1- (pyridin-3-ylsulfonyl) piperidin-3-yl] cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 1. LCMS: (M + H) ⁺ = 352.1.

Example 53

N-[(3S) -1- (2-thienylsulfonyl) piperidin-3-yl] cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 7. LCMS: (M + H) ⁺ = 357.1.

Example 54

N-{(3S) -1-[(3,5-dimethylisoxazol-4-yl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 1. LCMS: (M + H) ⁺ = 370.1.

Example 55

N-{(3S) -1-[(4-phenoxypyridin-3-yl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 1. LCMS: (M + H) ⁺ = 444.1.

Example 56

N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} cyclopentanecarboxamide

Step 1: (3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-amine hydrochloride

 3-Chloro-2-methylbenzenesulfonyl chloride (455 mg, 2.02 mmol) at 0 ° C. tert-butyl (3S) -piperidin-3-ylcarbamate (400.0 mg, 2.00 in acetonitrile (5.0 mL) mmol) and N, N-diisopropylethylamine (355 μl, 204 mmol). After 10 minutes the ice water bath was removed and the mixture was stirred at rt overnight. The solvent was evaporated. The residue was treated with 4.0 M hydrogen chloride in 1,4-dioxane (3.0 mL) for 1 hour at room temperature. The solvent was removed under reduced pressure to give the product which was used directly in the next step without further purification.

Step 2: N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} cyclopentanecarboxamide

(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidine-3-amine hydrochloride (50 umol) in acetonitrile (1.00 mL) was diluted with N, N-diisopropylethylamine ( 20.0 μl, 115 umol). To the obtained solution was added cyclopentanecarbonyl chloride (7.0 mg, 52.5 μmol) at room temperature. The mixture was stirred at rt for 1 h, diluted with DMSO (0.8 mL) and adjusted to pH = 2.0 using TFA. The resulting solution was purified by preparative HPLC to give the desired product N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} cyclopentanecarboxamide. . LCMS: (M + H) ⁺ = 385.1 / 387.1.

Example 57

N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} adamantane-1-carboxamide

This compound was prepared using a process similar to the process of Example 56. LCMS: (M + H) ⁺ = 451.1 / 453.1.

Example 58

N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -2-methylpropanamide

This compound was prepared using a process similar to the process of Example 56. LCMS: (M + H) ⁺ = 359.1 / 361.0.

Example 59

N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -2,2-dimethylpropanamide

This compound was prepared using a process similar to the process of Example 56. LCMS: (M + H) ⁺ = 373.1 / 375.1.

Example 60

N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -2,2-diphenylacetamide

This compound was prepared using a process similar to the process of Example 56. LCMS: (M + H) ⁺ = 483.1 / 485.1.

Example 61

1-acetyl-N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} piperidine-4-carboxamide

This compound was prepared using a process similar to the process of Example 56. LCMS: (M + H) ⁺ = 442.1 / 444.1.

Example 62

N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -1- (4-chlorophenyl) cyclopentanecarboxamide

This compound was prepared using a process similar to the process of Example 56. LCMS: (M + H) ⁺ = 495.1 / 497.1.

Example 63

N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -1-methylcyclohexanecarboxamide

N-methyl morpholine (40.0 μl) was added to BOP (22.3 mg, 50 μmol), 1-methylcyclohexanecarboxylic acid (7.1 mg, 50 μmol) and (3S) -1-[(3-chloro -2-methylphenyl) sulfonyl] -piperidin-3-amine hydrochloride (50 μmol) was added to the mixture. The mixture was stirred at rt for 3 h, then adjusted to PH = 2.0 using TFA and diluted with DMSO (1100 μl). The resulting solution was purified by preparative HPLC to give the desired product N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -1-methylcyclohexanecarbox Obtained amide. LCMS: (M + H) ⁺ = 413.1 / 415.1.

Example 64

N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -3-methoxycyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 56. LCMS: (M + H) ⁺ = 429.1 / 431.1.

Example 65

Trans-N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -3-methoxycyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 56. LCMS: (M + H) ⁺ = 429.1 / 431.1.

Example 66

N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -4-methoxycyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 56. LCMS: (M + H) ⁺ = 429.1 / 431.1.

Example 67

Trans-N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -4-methoxycyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 56. LCMS: (M + H) ⁺ = 429.1 / 431.1.

Example 68

N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -4-hydroxycyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 56. LCMS: (M + H) ⁺ = 415.1 / 417.1.

Example 69

Trans-N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -4-hydroxycyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 56. LCMS: (M + H) ⁺ = 415.1 / 417.1.

Example 70

N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -1-phenylcyclopropanecarboxamide

This compound was prepared using a process similar to the process of Example 56. LCMS: (M + H) ⁺ = 433.1 / 435.1.

Example 71

N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} biphenyl-2-carboxamide

This compound was prepared using a process similar to the process of Example 56. LCMS: (M + H) ⁺ = 469.0 / 471.1.

Example 72

N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} cycloheptancarboxamide

This compound was prepared using a process similar to the process of Example 56. LCMS: (M + H) ⁺ = 413.1 / 415.1.

Example 73

Tert-butyl (3S) -3-[((3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-ylamino) carbonyl] piperidine-1-carboxyl Rate

This compound was prepared using a process similar to the process of Example 56. LCMS: (M + Na) ⁺ = 522.1 / 524.1; (M-56) ⁺ = 444.1 / 446.1.

Example 74

(3S) -N- (3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl-1- (methylsulfonyl) piperidine-3-carboxamide

Tert-butyl (3S) -3-[((3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-ylamino) -carbonyl] -piperidine-1 Carboxylate (10.0 mg, 200 μmol, prepared as in Example 73) was treated with 4.0 M hydrogen chloride in 1,4-dioxane (0.5 mL) for 1 hour at room temperature. The solvent was evaporated in vacuo and the residue was dissolved in acetonitrile (0.8 mL) and treated with diisopropylethylamine (20.0 μL) and methylsulfonyl chloride (5.0 μL). The resulting mixture was stirred at rt for 30 min. The crude reaction mixture was diluted with MeOH (1.3 mL), adjusted to pH 2 using TFA and purified by preparative HPLC to afford the desired product. LCMS: (M + H) ⁺ = 478.0 / 480.0.

Example 75

Methyl (3S) -3-[((3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-ylamino) carbonyl] piperidine-1-carboxylate

This compound was prepared using a process similar to the process of Example 74. LCMS: (M + H) ⁺ = 458.1 / 460.1.

Example 76

(3S) -N- (3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl-1- (methylsulfonyl) piperidine-3-carboxamide

This compound was prepared using a process similar to the process of Example 74. LCMS: (M + H) ⁺ = 478.0 / 480.0.

Example 77

(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] -N- (3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-ylpiperidine -3-carboxamide

This compound was prepared using a process similar to the process of Example 74. LCMS: (M + H) ⁺ = 588.1 / 590.1.

Example 78

N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} benzamide

This compound was prepared using a process similar to the process of Example 56. LCMS: (M + H) ⁺ = 393.1 / 395.0.

Example 79

N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -2-methylbenzamide

This compound was prepared using a process similar to the process of Example 56. LCMS: (M + H) ⁺ = 407.1 / 409.1.

Example 80

N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -2-chlorobenzamide

This compound was prepared using a process similar to the process of Example 56. LCMS: (M + H) ⁺ = 427.0 / 429.0.

Example 81

N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -3-fluorobenzamide

This compound was prepared using a process similar to the process of Example 56. LCMS: (M + H) ⁺ = 411.0 / 413.0.

Example 82

N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -3-methoxybenzamide

This compound was prepared using a process similar to the process of Example 56. LCMS: (M + H) ⁺ = 423.1 / 425.1.

Example 83

N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -3- (trifluoromethyl) benzamide

This compound was prepared using a process similar to the process of Example 56. LCMS: (M + H) ⁺ = 461.0 / 463.1.

Example 84

N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} pyridine-2-carboxamide

This compound was prepared using a process similar to the process of Example 56. LCMS: (M + H) ⁺ = 394.0 / 396.0.

Example 85

N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} pyridine-3-carboxamide

This compound was prepared using a process similar to the process of Example 56. LCMS: (M + H) ⁺ = 394.0 / 396.0.

Example 86

N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} pyridine-4-carboxamide

This compound was prepared using a process similar to the process of Example 56. LCMS: (M + H) ⁺ = 394.0 / 396.0.

Example 87

N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -4-methoxybenzamide

This compound was prepared using a process similar to the process of Example 56. LCMS: (M + H) ⁺ = 423.1 / 425.1.

Example 88

N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -3-phenoxybenzamide

This compound was prepared using a process similar to the process of Example 56. LCMS: (M + H) ⁺ = 485.1 / 487.1.

Example 89

N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -1-naphthamide

This compound was prepared using a process similar to the process of Example 56. LCMS: (M + H) ⁺ = 443.1 / 445.0.

Example 90

N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -2-methoxybenzamide

This compound was prepared using a process similar to the process of Example 56. LCMS: (M + H) ⁺ = 423.1 / 425.0.

Example 91

N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -2,5-difluorobenzamide

This compound was prepared using a process similar to the process of Example 56. LCMS: (M + H) ⁺ = 429.0 / 431.0.

Example 92

N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -2-fluoro-4- (trifluoromethyl) benzamide

This compound was prepared using a process similar to the process of Example 56. LCMS: (M + H) ⁺ = 479.0 / 481.0.

Example 93

N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -4-fluoro-3- (trifluoromethyl) benzamide

This compound was prepared using a process similar to the process of Example 56. LCMS: (M + H) ⁺ = 479.0 / 481.0.

Example 94

N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -2-fluoro-5- (trifluoromethyl) benzamide

This compound was prepared using a process similar to the process of Example 56. LCMS: (M + H) ⁺ = 479.0 / 481.0.

Example 95

N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -3,5-difluorobenzamide

This compound was prepared using a process similar to the process of Example 56. LCMS: (M + H) ⁺ = 429.0 / 431.0.

Example 96

N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -2,6-difluorobenzamide

This compound was prepared using a process similar to the process of Example 56. LCMS: (M + H) ⁺ = 429.0 / 431.0.

Example 97

4-hydroxy-N-[(3S) -1-phenylpiperidin-3-yl] cyclohexanecarboxamide

Step 1: tert-butyl [(3S) -1-phenylpiperidin-3-yl] carbamate

Tert-butyl (3S) -piperidin-3-ylcarbamate 0.200 g, 0.00100 mol) in dimethyl sulfoxide (4.0 mL, 0.056 mol), bromobenzene (211 μL, 0.00200 mol) and sodium tertiary- The solution was heated to 200 ° C. for 5 minutes by irradiating the mixture of butoxide 192 mg, 0.00200 mol) with microwave. The reaction mixture was diluted with water (10 mL) and the solution extracted with methylene chloride (5 x 5 mL). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated to give the desired product which was used directly in the next step without further purification. LCMS: (M + H) ⁺ = 177.2.

Step 2: (3S) -1-phenylpiperidin-3-amine dihydrochloride

Tert-butyl [(3S) -1-phenylpiperidin-3-yl] carbamate (48 mg, 0.00017 mol) was dissolved in 2 mL of 4.0 M HCl in dioxane and the resulting solution was stirred overnight at room temperature. The volatiles were removed in vacuo to afford the desired product as a residue, which was used in the next step without further purification.

Step 3: 4-hydroxy-N-[(3S) -1-phenylpiperidin-3-yl] cyclohexanecarboxamide

4-Methylmorpholine (23 μL 0.00021 mol) was added to (3S) -1-phenylpiperidin-3-amine dihydrochloride (0.042 mmol, 0.000042 mol) in N, N-dimethylformamide (0.5 mL, 0.006 mol). ), 4-hydroxycyclohexanecarboxylic acid (6.7 mg, 0.000046 mol) and benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (0.020 g, 0.000046 mol). The reaction mixture was stirred at rt overnight. The reaction mixture was diluted with methanol (0.8 mL) and adjusted to pH = 2.0 using TFA. The crude product was purified by preparative LCMS. LCMS: (M + H) ⁺ = 303.2.

Example 98

4-methoxy-N-[(3S) -1-phenylpiperidin-3-yl] cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 97. LCMS: (M + H) ⁺ = 317.3.

Example 99

4- (hydroxymethyl) -N-[(3S) -1-phenylpiperidin-3-yl] cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 97. LCMS: (M + H) ⁺ = 317.3.

Example 100

2-hydroxy-N-[(3S) -1-phenylpiperidin-3-yl] bicyclo [3.2.1] octane-6-carboxamide

This compound was prepared using a process similar to the process of Example 97. LCMS: (M + H) ⁺ = 329.3.

Example 101

N-[(3S) -1-phenylpiperidin-3-yl] adamantane-1-carboxamide

This compound was prepared using a process similar to the process of Example 97. LCMS: (M + H) ⁺ = 339.3.

Example 102

3-hydroxy-N-[(3S) -1-phenylpiperidin-3-yl] adamantane-1-carboxamide

This compound was prepared using a process similar to the process of Example 97. LCMS: (M + H) ⁺ = 355.3.

Example 103

N-[(3S) -1-phenylpiperidin-3-yl] cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 97. LCMS: (M + H) ⁺ = 287.3.

Example 104

1-methyl-N-[(3S) -1-phenylpiperidin-3-yl] cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 97. LCMS: (M + H) ⁺ = 301.3.

Example 105

4-methyl-N-[(3S) -1-phenylpiperidin-3-yl] cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 97. LCMS: (M + H) ⁺ = 301.3.

Example 106

4-ethyl-N-[(3S) -1-phenylpiperidin-3-yl] cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 97. LCMS: (M + H) ⁺ = 315.3.

Example 107

3-methoxy-N-[(3S) -1-phenylpiperidin-3-yl] cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 97. LCMS: (M + H) ⁺ = 317.3.

Example 108

4-methoxy-N-[(3S) -1-phenylpiperidin-3-yl] cyclohexanecarboxamide

This compound was prepared using a process similar to the process of Example 97. LCMS: (M + H) ⁺ = 317.3.

Example 109

N-[(3S) -1-phenylpiperidin-3-yl] bicyclo [2.2.1] heptane-2-carboxamide

This compound was prepared using a process similar to the process of Example 97. LCMS: (M + H) ⁺ = 299.3.

Example 110

N-[(3S) -1-phenylpiperidin-3-yl] cycloheptancarboxamide

This compound was prepared using a process similar to the process of Example 97. LCMS: (M + H) ⁺ = 301.3.

Example 111

N-[(3S) -1-phenylpiperidin-3-yl] -1,2,3,4-tetrahydronaphthalene-2-carboxamide

This compound was prepared using a process similar to the process of Example 97. LCMS: (M + H) ⁺ = 335.2.

Example 112

2-methyl-N-[(3S) -1-phenylpiperidin-3-yl] benzamide

This compound was prepared using a process similar to the process of Example 97. LCMS: (M + H) ⁺ = 295.2.

Example 113

5-chloro-2-methyl-N-[(3S) -1-phenylpiperidin-3-yl] benzamide

This compound was prepared using a process similar to the process of Example 97. LCMS: (M + H) ⁺ = 329.2 / 331.2.

Example 114

N-[(3S) -1-phenylpiperidin-3-yl] biphenyl-4-carboxamide

This compound was prepared using a process similar to the process of Example 97. LCMS: (M + H) ⁺ = 357.2.

Example 115

3-methoxy-N-[(3S) -1-phenylpiperidin-3-yl] benzamide

This compound was prepared using a process similar to the process of Example 97. LCMS: (M + H) ⁺ = 311.2.

Example 116

4-methoxy-N-[(3S) -1-phenylpiperidin-3-yl] benzamide

This compound was prepared using a process similar to the process of Example 97. LCMS: (M + H) ⁺ = 311.2.

Example 117

4-phenoxy-N-[(3S) -1-phenylpiperidin-3-yl] benzamide

This compound was prepared using a process similar to the process of Example 97. LCMS: (M + H) ⁺ = 373.2.

Example 118

2- (2-methyl-1H-indol-3-yl) -N-[(3S) -1-phenylpiperidin-3-yl] acetamide

This compound was prepared using a process similar to the process of Example 97. LCMS: (M + H) ⁺ = 348.2.

Example 119

N-[(3S) -1-phenylpiperidin-3-yl] -1H-indole-3-carboxamide

This compound was prepared using a process similar to the process of Example 97. LCMS: (M + H) ⁺ = 320.2.

Example 120

N-[(3S) -1-phenylpiperidin-3-yl] -1H-indole-2-carboxamide

This compound was prepared using a process similar to the process of Example 97. LCMS: (M + H) ⁺ = 320.2.

Example 121

1-methyl-N-[(3S) -1-phenylpiperidin-3-yl] -1H-indole-2-carboxamide

This compound was prepared using a process similar to the process of Example 97. LCMS: (M + H) ⁺ = 334.2.

Example 122

2-methyl-N-[(3S) -1-phenylpiperidin-3-yl] quinoline-3-carboxamide

This compound was prepared using a process similar to the process of Example 97. LCMS: (M + H) ⁺ = 346.2.

Example 123

N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} piperidine-1-carboxamide

Step 1: tert-butyl {(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} carbamate

Of tert-butyl (3S) -piperidin-3-ylcarbamate (499 mg, 0.00249 mol; CNH Technologies) and triethylamine (0.52 mL, 0.0037 mol) dissolved in methylene chloride (5.0 mL, 0.078 mol) The solution was cooled to 0 ° C. and 3-chloro-2-methylbenzenesulfonyl chloride (0.62 g, 0.0027 mol) (6:56) was added to the solution. After stirring for 10 minutes, the reaction mixture was gradually warmed to room temperature with stirring for 24 hours. The reaction was quenched with water (1:09), diluted with EtOAc and 0.1N HCl and washed with brine. The layers were separated and the organic layer was washed with saturated sodium bicarbonate, brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to afford 1.03 g of the desired product as a white solid. ¹ HNMR confirmed that the desired product was isolated.

Step 2: (3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-amine

Tert-butyl (3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidine dissolved in trifluoroacetic acid (1.0 mL, 0.013 mol) in methylene chloride (3.0 mL, 0.047 mol) To a solution of -3-ylcarbamate (1.03 g, 0.00265 mol). After stirring for 2 hours, the volatiles were removed in vacuo, the residue was dissolved in methylene chloride, washed with 1N NaOH, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give 828 mg of the desired product as a white solid. It was. ¹ H NMR confirmed the separation of the desired product.

Step 3: 4-nitrophenyl {(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} carbamate

(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-amine (404 mg, 0.00140 mol) is dissolved in methylene chloride (1.0E1 mL, 0.16 mol), and triethyl Amine (0.39 mL, 0.0028 mol) and p-nitrophenyl chloroformate (342 mg, 0.00170 mol) were added. After stirring for 4 hours at room temperature, the reaction mixture was washed with 0.1N HCl (2 × 2 mL) and the combined aqueous phases were washed with DCM. The combined organic phases were dried (MgSO ₄ ), filtered and the volatiles were removed in vacuo to give 691 mg of the desired product as a yellow solid. ¹ H NMR confirmed the separation of the desired product. LCMS: M + H = 454.1 / 456.1. The product was used in the next step without further steps.

Step 4: N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} piperidine-1-carboxamide

4-nitrophenyl {(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperi dissolved in piperidine (11 μl, 0.00011 mol) in tetrahydrofuran (0.5 mL, 0.006 mol) Din-3-yl} carbamate (25 mg, 0.000055 mol) was added to the solution. After 18 hours, the volatiles were removed and the residue was dissolved in MeCN / H ₂ O and purified by preparative HPLC to give 19 mg of the desired product as a white powder. ¹ H NMR confirmed the separation of the desired product. LCMS: M + H = 400.2 / 402.2.

Example 124

N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -4-hydroxypiperidine-1-carboxamide

This compound was prepared using a process similar to the process of Example 123. LCMS: (M + H) ⁺ = 416.2 / 418.1.

Example 125

N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} morpholine-4-carboxamide

This compound was prepared using a process similar to the process of Example 123. LCMS: (M + H) ⁺ = 402.1 / 404.1.

Example 126

N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} thiomorpholine-4-carboxamide

This compound was prepared using a process similar to the process of Example 123. LCMS: (M + H) ⁺ = 418.1 / 420.1.

Example 127

N-{(3S) -1-[(3-chloro-2-fluorophenyl) sulfonyl] piperidin-3-yl} piperidine-1-carboxamide

This compound was prepared using a process similar to the process of Example 123. LCMS: (M + H) ⁺ = 404.1 / 406.1.

Example 128

N-{(3S) -1-[(3-chloro-2-fluorophenyl) sulfonyl] piperidin-3-yl} -4-hydroxypiperidine-1-carboxamide

This compound was prepared using a process similar to the process of Example 123. LCMS: (M + H) ⁺ = 420.1 / 422.1.

Example 129

N-{(3S) -1-[(3-chloro-2-fluorophenyl) sulfonyl] piperidin-3-yl} morpholine-4-carboxamide

This compound was prepared using a process similar to the process of Example 123. LCMS: (M + H) ⁺ = 406.1 / 408.1.

Example 130

N-{(3S) -1-[(3-chloro-2-fluorophenyl) sulfonyl] piperidin-3-yl} thiomorpholine-4-carboxamide

This compound was prepared using a process similar to the process of Example 123. LCMS: (M + H) ⁺ = 422.1 / 424.1.

Example 131

N-{(3S) -1-[(2,6-dichlorophenyl) sulfonyl] piperidin-3-yl} piperidine-1-carboxamide

This compound was prepared using a process similar to the process of Example 123. LCMS: (M + H) ⁺ = 420.1 / 422.1.

Example 132

N-{(3S) -1-[(2,6-dichlorophenyl) sulfonyl] piperidin-3-yl} -4-hydroxypiperidine-1-carboxamide

This compound was prepared using a process similar to the process of Example 123. LCMS: (M + H) ⁺ = 436.1 / 438.1.

Example 133

N-{(3S) -1-[(2,6-dichlorophenyl) sulfonyl] piperidin-3-yl} morpholine-4-carboxamide

This compound was prepared using a process similar to the process of Example 123. LCMS: (M + H) ⁺ = 422.1 / 424.1.

Example 134

N-{(3S) -1-[(2,6-dichlorophenyl) sulfonyl] piperidin-3-yl} thiomorpholine-4-carboxamide

This compound was prepared using a process similar to the process of Example 123. LCMS: (M + H) ⁺ = 438.1 / 440.0.

Example 135

N-{(3S) -1-[(3-chloro-2-fluorophenyl) sulfonyl] piperidin-3-yl} thiomorpholine-4-carboxamide 1-oxide

m-chloroperbenzoic acid (61mg, 0.00027mol) dissolved in methylene chloride (5.0mL, 0.078mol) N-{(3S) -1-[(3-chloro-2-fluorophenyl) sulfonyl] piperi Din-3-yl} thiomorpholine-4-carboxamide (75 mg, 0.00018 mol) was added to the solution and the solution was stirred for 16 hours. Saturated sodium bisulfite was added to quench the reaction and the reaction mixture was stirred for an additional 2 hours. The solution was washed thoroughly with 1N NaOH, the organic layer obtained was washed with brine, dried (Na ₂ SO ₄ ), filtered and the volatiles removed in vacuo to yield 62 mg of the desired product as a white solid, Purification by preparative HPLC. LCMS (M + H) ⁺ = 438.1 / 440.1.

Example 136

N-{(3S) -1-[(3-chloro-2-fluorophenyl) sulfonyl] piperidin-3-yl} thiomorpholine-4-carboxamide 1,1-dioxide

This compound was prepared using a process similar to the process of Example 135. LCMS: (M + H) ⁺ = 454.1 / 456.1.

Example 137

N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} thiomorpholine-4-carboxamide 1,1-dioxide

This compound was prepared using a process similar to the process of Example 135. LCMS: (M + H) ⁺ = 450.1 / 452.1.

Example 138

N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} thiomorpholine-4-carboxamide 1-oxide

This compound was prepared using a process similar to the process of Example 135. LCMS: (M + H) ⁺ = 434.1 / 436.0.

Example 139

N-{(3S) -1-[(2,6-dichlorophenyl) sulfonyl] piperidin-3-yl} thiomorpholine-4-carboxamide 1-oxide

This compound was prepared using a process similar to the process of Example 135. LCMS: (M + H) ⁺ = 454.0 / 456.1.

Example 140

N-{(3S) -1-[(2,6-dichlorophenyl) sulfonyl] piperidin-3-yl} thiomorpholine-4-carboxamide 1,1-dioxide

This compound was prepared using a process similar to the process of Example 135. LCMS: (M + H) ⁺ = 470.0 / 472.0.

Example 141

4-hydroxy-N-[(3S) -1-phenylpiperidin-3-yl] adamantane-1-carboxamide

Step 1: tert-butyl (3S) -3-{[(4-oxo-1-adamantyl) carbonyl] amino} piperidine-1-carboxylate

Oxalyl chloride (233 μl, 0.00275 mol) was added to 4-oxoadamantane-1-carboxylic acid (97.08 mg, 0.0004998 mol) in methylene chloride (10 mL) at room temperature followed by the addition of 2 drops of DMF. The mixture was stirred at rt for 2 h and then the volatiles were removed under reduced pressure. The residue was evaporated twice by azeotropically mixing with toluene and the obtained residue was dissolved in DCM (10 mL). To this solution was added tert-butyl (3S) -3-aminopiperidine-1-carboxylate (100.1 mg, 0.0004998 mol) and N, N-diisopropylethylamine (0.18 mL, 0.0010 mol). After stirring for 1 h at rt, the reaction mixture was washed with DCM (100 mL) and washed with water, 1N HCl and brine. The organic phase was dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo to afford the desired product. LCMS: (M-t-Bu + H) ⁺ = 321.2.

Step 2: tert-butyl (3S) -3-{[(4-hydroxy-1-adamantyl) carbonyl] amino} piperidine-1-carboxylate

1.0 M L-selectride ^R in tetrahydrofuran (0.50 mL) was tert-butyl (3S) -3-{[(4-oxo-1- in tetrahydrofuran (1.0 mL, 0.012 mol) at −78 ° C. To a solution of adamantyl) carbonyl] amino} piperidine-1-carboxylate (75 mg, 0.00020 mol). The mixture was stirred at −78 ° C. for 30 minutes and then quenched with ice water. The mixture was extracted with ethyl acetate (3 x 2 mL). The combined organic phases were washed with brine (2 mL), dried over Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The residue was purified by Combiflash eluting with ethyl acetate / hexanes to afford the desired product. LCMS: (M-t-Bu + H) ⁺ = 323.2.

Step 3: 4-hydroxy-N-[(3S) -piperidin-3-yl] adamantane-1-carboxamide hydrochloride

Tert-butyl (3S) -3-{[(4-hydroxy-1-adamantyl) carbonyl] amino} piperidine-1-carboxylate (75 mg, 0.00020 mol) at room temperature for 1 hour 30 minutes Treatment with 4.0 M hydrogen chloride in, 4-dioxane (0.30 mL). The volatiles were evaporated and the residue was dried under reduced pressure to afford the desired product. LCMS: (M + H) ⁺ = 315.4.

Step 4: 4-hydroxy-N-[(3S) -1-phenylpiperidin-3-yl] adamantane-1-carboxamide

4-hydroxy-N-[(3S) -piperidin-3-yl] adamantane-1-carboxamide hydrochloride (15.7 mg, 0.0000500 mol) in dimethyl sulfoxide (0.50 mL, 0.0070 mol), A mixture of bromobenzene (10.5 μl, 0.000100 mol) and sodium tert-butoxide (9.61 mg, 0.000100 mol) was irradiated with microwave at 200 ° C. for 5 minutes. The mixture was diluted with methanol (1.3 mL) and adjusted to pH = 2.0 using TFA. The resulting solution was purified by preparative HPLC to give horizontal and vertical hydroxyl products. LCMS: (M + H) ⁺ = 355.2.

Example 142

N-[(3S) -1-phenylpiperidin-3-yl] -1-pyridin-4-ylcyclobutanecarboxamide

This compound was prepared using a synthesis similar to that described in Examples 97, Steps 1-3. LCMS: (M + H) ⁺ = 336.0.

Example 143

N-[(3S) -1-phenylpiperidin-3-yl] -1-pyridin-3-ylcyclobutanecarboxamide

This compound was prepared using a synthesis similar to that described in Examples 97, Steps 1-3. LCMS: (M + H) ⁺ = 336.0.

Example 144

1-phenyl-N-[(3S) -1-phenylpiperidin-3-yl] cyclopropanecarboxamide

This compound was prepared using the synthesis of Example 97, a procedure similar to that described in steps 1-3. LCMS: (M + H) ⁺ = 321.1.

Example 145

Methyl 4- {3-fluoro-4- [1-([(3S) -1-phenylpiperidin-3-yl] aminocarbonyl) cyclopropyl] phenyl} piperazin-1-carboxylate

Step 1. 1- (4-Bromo-2-fluorophenyl) cyclopropanecarboxylic acid

(4-bromo-2-fluorophenyl) acetonitrile (12.53 g, 0.05854 mol), benzyltriethylammonium chloride (0.9 g, 0.004 mol) and 1-bromo-2-chloro-ethane (9.70 mL, 0.117 mol) to a stirred mixture was added dropwise at 50 ° C. a 50% aqueous sodium hydroxide solution (21.00 mL, 0.5484 mol). After stirring for 16 hours, the reaction mixture was diluted with water, 1,2-ethanediol (65.00 mL, 1.166 mol) and 50% aqueous sodium hydroxide solution (5 mL). The resulting mixture was added at 100 ° C. for 16 hours. The reaction mixture was extracted with diethyl ether and the aqueous layer was acidified to pH about 2, the product was precipitated and collected by filtration and used in subsequent reaction without further purification.

Step 2. 1- {4- [4- (tert-Butoxycarbonyl) piperazin-1-yl] -2-fluorophenyl} cyclopropane carboxylic acid

1- (4-bromo-2-fluorophenyl) cyclopropanecarboxylic acid (2.390 g, 0.009225 mol) in 1,4-dioxane anhydride (30.0 mL, 0.384 mol), tert-butyl piperazine-1-carboxyl Rate (2.126g, 0.01107mol), sodium tert-butoxide (2.194g, 0.02214mol), palladium acetate (62mg, 0.00028mol) and 2- (di-t-butylphosphino) biphenyl (165mg, 0.000554 mol) was refluxed overnight (oil bath temperature 110 ° C.). The reaction mixture was poured into cold saturated NH ₄ Cl (60 mL), acidified to pH 6 with 1N HCl and extracted with ethyl acetate (2 ×). The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by combiflash eluting with 0-10% methanol in methylene chloride to give the product (1.762 g, yield 52%). LCMS: (Mt-Bu + H) ⁺ = 309.1.

Step 3. Tert-butyl 4- {3-fluoro-4- [1-([{(3S) -1-phenylpiperidin-3-yl] amino} carboni) cyclopropyl] phenyl} piperazine -1-carboxylate

This compound was prepared using a synthesis similar to that described in Examples 97, Steps 1-3. LCMS: (Mt-Bu + 2H) ⁺ = 467.1

Step 4. Methyl 4- {3-fluoro-4- [1-({[(3S) -1-phenylpiperidin-3-yl] amino} carbonyl) cyclopropyl] phenyl} piperazin-1- Carboxylate

This compound was prepared using a process similar to that described in Synthesis of Example 9, steps 2 and 3. LCMS: (M + H) ⁺ = 481.1

Example 146

Benzyl (3S) -3-{[(4-hydroxy-1-adamantyl) carbonyl] amino} piperidine-1-carboxylate

This compound was prepared using a synthesis similar to Example 9, steps 1 to 3, using appropriate carbonyl chloride. LCMS: (M + H) ⁺ = 413.2.

Example 147

4-hydroxy-N-{(3S) -1- [6- (trifluoromethyl) pyridin-2-yl] piperidin-3-yl} adamantane-1-carboxamide

This compound was prepared using a synthesis similar to that described in Examples 97, Steps 1-3. LCMS: (M + H) ⁺ = 424.2.

Example 148

4-hydroxy-N-{(3S) -1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-3-yl} adamantane-1-carboxamide

This compound was prepared using a synthesis similar to that described in Examples 97, Steps 1-3. LCMS: (M + H) ⁺ = 424.2.

Example 149

4-hydroxy-N-[(3S) -1- (5-nitropyridin-2-yl) piperidin-3-yl] adamantane-1-carboxamide

This compound was prepared using a synthesis similar to that described in Examples 97, Steps 1-3. LCMS: (M + H) ⁺ = 401.2.

Example 150

및

And

N-[(3S) -1- (5-cyanopyridin-2-yl) piperidin-3-yl] -4-hydroxyadamantane-1-carboxamide

This compound was prepared using a synthesis similar to that described in Examples 97, Steps 1-3. LCMS: (M + H) ⁺ = 381.1.

Example 151

6-((3S) -3-{[(4-hydroxy-1-adamantyl) carbonyl] amino} piperidin-1-yl) -N, N-dimethylnicotinamide

This compound was prepared using a synthesis similar to that described in Examples 97, Steps 1-3. LCMS: (M + H) ⁺ = 427.3.

Example 152

및

And

Methyl 6-((3S) -3-{[(4-hydroxy-1-adamantyl) carbonyl] amino} piperidin-1-yl) nicotinate

This compound was prepared using a synthesis similar to that described in Examples 97, Steps 1-3. LCMS: (M + H) ⁺ = 414.2.

Example 153

및

And

4-hydroxy-N-{(3S) -1- [4- (trifluoromethyl) phenyl] piperidin-3-yl} adamantane-1-carboxamide

4-hydroxy-N-[(3S) -piperidin-3-yl] adamantane-1-carboxamide (20.9 mg, 0.0000750 mol), 1-bromo-4- (trifluoromethyl) Benzene (25.3 mg, 0.000112 mol), sodium tert-butoxide (10.8 mg, 0.000112 mol), palladium acetate (0.50 mg, 0.0000022 mol) and 2- (di-t-butylphosphino) biphenyl (1.3 mg, 0.0000045 mol) of the mixture was degassed and charged with nitrogen. 1,4-dioxane (0.75 mL, 0.0096 mol) was added to the mixture, and the obtained mixture was refluxed for 16 hours. After cooling to ambient temperature, the reaction mixture was filtered and the filtrate was adjusted to pH = 2.0 using TFA and purified by preparative HPLC to afford the desired product. LCMS: (M + H) ⁺ = 423.2.

Example 154

및

And

4-hydroxy-N-{(3S) -1- [4- (trifluoromethoxy) phenyl] piperidin-3-yl} adamantane-1-carboxamide

This compound was prepared using a process similar to that described in the synthesis of Example 153. LCMS: (M + H) ⁺ = 439.2.

Example 155

및

And

N-{(3S) -1- [4- (benzyloxy) phenyl] piperidin-3-yl} -4-hydroxyadamantane-1-carboxamide

This compound was prepared using a process similar to that described in the synthesis of Example 153. LCMS: (M + H) ⁺ = 461.3.

Example 156

N-[(3S) -1- (3-fluoropyridin-4-yl) piperidin-3-yl] -4-hydroxyadamantane-1-carboxamide

This compound was prepared using a synthesis similar to that described in Examples 97, Steps 1-3. LCMS: (M + H) ⁺ = 374.2.

Example 157

4-hydroxy-N-[(3S) -1- (1,3-thiazol-2-yl) piperidin-3-yl] adamantane-1-carboxamide

This compound was prepared using a synthesis similar to that described in Examples 97, Steps 1-3. LCMS: (M + H) ⁺ = 362.2.

Example 158

및

And

(3S) -3-{[(4-hydroxy-1-adamantyl) carbonyl] amino} -N-phenylpiperidine-1-carboxamide

This compound was prepared using a process analogous to the synthesis of Example 9, the procedure described in steps 1 to 3, using the appropriate carbonyl chloride reagent. LCMS: (M + H) ⁺ = 398.2.

Example 159

N-[(3S) -1-benzoylpiperidin-3-yl] -4-hydroxyadamantane-1-carboxamide

This compound was prepared using a process analogous to the synthesis of Example 9, the procedure described in steps 1 to 3, using the appropriate carbonyl chloride reagent. LCMS: (M + H) ⁺ = 383.2.

Example 160

4-hydroxy-N-[(3S) -1- (4-pyridin-3-ylphenyl) piperidin-3-yl] adamantane-1-carboxamide

This compound was prepared using a synthesis similar to that described in Examples 97, Steps 1-3. LCMS: (M + H) ⁺ = 432.2.

Example 161

N-{(3S) -1- [5- (4-chlorophenyl) pyridin-2-yl] piperidin-3-yl} -4-hydroxyadamantane-1-carboxamide

This compound was prepared using a synthesis similar to that described in Examples 97, Steps 1-3. LCMS: (M + H) ⁺ = 466.2 / 468.2.

Example 162

4-hydroxy-N-[(3S) -1- (4-pyridin-2-ylphenyl) piperidin-3-yl] adamantane-1-carboxamide

This compound was prepared using a synthesis similar to that described in Examples 97, Steps 1-3. LCMS: (M + H) ⁺ = 432.2.

Example 163

(1S, 5S) -3-hydroxy-N-[(3S) -1- (1-naphthylsulfonyl) piperidin-3-yl] -8-azabicyclo [3.2.1] octane-8- Carboxamide

Step 1. tert-Butyl (3S) -3-[(4-nitrophenoxy) carbonyl] aminopiperidine-1-carboxylate

This compound was prepared using a process analogous to that described in Synthesis of Example 123, Step 4, starting from tert-butyl (3S) -3-aminopiperidine-1-carboxylate. LCMS: (M + Na) ⁺ = 388.1; (M + H-Boc) ⁺ =. 266.1.

Step 2. Tert-Butyl (3S) -3-({[(1S, 5S) -3-hydroxy-8-azabicyclo [3.2.1] oct-8-yl] carbonyl} amino) piperi Dean-1-carboxylate

This compound is tert-butyl (3S) -3-{[(4-nitrophenoxy) -carbonyl] -amino} -piperidine-1-carboxylate and (1S, 5S) -8-azabicyclo Starting from [3.2.1] octan-3-ol hydrochloride, the synthesis of Example 123 was made using a process similar to that described in Step 4. LCMS: (M + Na) ⁺ = 376.2.

Step 3. (1S, 5S) -3-Hydroxy-N-[(3S) -piperidin-3-yl] -8-azabicyclo [3.2.1] octane-8-carboxamide hydrochloride

This compound was prepared using a process similar to that described in Synthesis of Example 97, Step 2. LCMS: (M + H) ⁺ = 290.3

Step 4. (1S, 5S) -3-hydroxy-N-[(3S) -1- (1-naphthylsulfonyl) piperidin-3-yl] -8-azabicyclo [3.2.1] octane -8-carboxamide

Synthesis of Example 123, prepared using a process similar to that described in Step 1. LCMS: (M + H) ⁺ = 444.2.

Example 164

(1S, 5S) -N-{(3S) -1-[(2,6-dichlorophenyl) sulfonyl] piperidin-3-yl} -3-hydroxy-8-azabicyclo [3.2.1 ] Octane-8-carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 163, steps 1-4. LCMS: (M + H) ⁺ = 462.1 / 464.1.

Example 165

(1S, 5S) -N-{(3S) -1-[(3-chloro-2-fluorophenyl) sulfonyl] piperidin-3-yl} -3-hydroxy-8-azabicyclo [ 3.2.1] octane-8-carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 163, steps 1-4. LCMS: (M + H) ⁺ = 446.1 / 448.1.

Example 166

(1S, 5S) -N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -3-hydroxy-8-azabicyclo [3.2. 1] octane-8-carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 163, steps 1-4. LCMS: (M + H) ⁺ = 442.1 / 444.1.

Example 167

(1S, 5S) -N-{(3S) -1-[(3-chlorophenyl) sulfonyl] piperidin-3-yl} -3-hydroxy-8-azabicyclo [3.2.1] octane -8-carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 163, steps 1-4. LCMS: (M + H) ⁺ = 428.1 / 430.1.

Example 168

(1S, 5S) -3-hydroxy-N-{(3S) -1-[(3-methylphenyl) sulfonyl] piperidin-3-yl} -8-azabicyclo [3.2.1] octane- 8-carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 163, steps 1-4. LCMS: (M + H) ⁺ = 408.2.

Example 169

(1S, 5S) -N-{(3S) -1-[(2-fluorophenyl) sulfonyl] piperidin-3-yl} -3-hydroxy-8-azabicyclo [3.2.1] Octane-8-Carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 163, steps 1-4. LCMS: (M + H) ⁺ = 412.2.

Example 170

(1S, 5S) -3-hydroxy-N-{(3S) -1-[(2-methylphenyl) sulfonyl] piperidin-3-yl} -8-azabicyclo [3.2.1] octane- 8-carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 163, steps 1-4. LCMS: (M + H) ⁺ = 408.1.

Example 171

N-((3S) -1- {4- [2- (diethylamino) -2-oxoethoxy] phenyl} piperidin-3-yl) -4-hydroxyadamantane-1-carbox amides

Step 1. Benzyl (3S) -3-{[(4-oxo-1-adamantyl) carbonyl] amino} piperidine-1-carboxylate

Oxalyl chloride (1.50 mL, 0.0177 mol) was added to 4-oxoadamantane-1-carboxylic acid (583 mg, 0.00300 mol) in methylene chloride (10 mL), followed by two drops of DMF. The mixture was stirred at rt for 2 h. The volatiles were evaporated under reduced pressure and the residue was evaporated twice by azeotropically mixing with toluene. The residue was dissolved in DCM (10 mL), and in this solution benzyl (3S) -3-aminopiperidine-1-carboxylate hydrochloride (812.6 mg, 0.003001 mol) and N, N-diisopropylethylamine (1.20 mL, 0.00689 mol) was added. The mixture was stirred at rt for 1 h. The reaction mixture was diluted with DCM (100 mL) and washed with water, 1N HCl and brine. The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated to give the desired product.

Step 2. Benzyl (3S) -3-{[(4-hydroxy-1-adamantyl) carbonyl] amino} piperidine-1-carboxylate

Sodium borohydride (20.0 mg, 0.000529 mol) was benzyl (3S) -3-{[(4-oxo-1-adamantyl) carbonyl] amino} piperidine in methanol (2.0 mL, 0.049 mol) at room temperature. To a solution of -1-carboxylate (102.8 mg, 0.0002504 mol). After stirring at room temperature for 30 minutes, the reaction mixture was diluted with ethyl acetate (5 mL), washed with 1N NaOH, water and brine, dried over Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The residue was purified by combiflash with ethyl acetate / hexanes to give a mixture of two isomers with a ratio of 1: 1.

Step 3. 4-Hydroxy-N-[(3S) -piperidin-3-yl] adamantane-1-carboxamide

Benzyl (3S) -3-[(4-hydroxy-1-adamantyl) carbonyl] aminopiperidine-1-carboxylate (0.900 g, 0.00218 mol) in methanol (15 mL) was blown for 2 hours. Hydrogenated with palladium on barium sulfate (25 mg, 0.00023 mol) under a hydrogen atmosphere. The mixture was filtered and the filtrate was concentrated. The residue was dried under high vacuum to afford the desired product. LCMS: (M + H) ⁺ = 279.1.

Step 4. N-((3S) -1- {4- [2- (diethylamino) -2-oxoethoxy] phenyl} piperidin-3-yl) -4-hydroxyadamantane-1 Carboxamide

4-hydroxy-N-[(3S) -piperidin-3-yl] adamantane-1-carboxamide (18.1 mg, 0.0000650 mol), 2- (4-chlorophenoxy) -N, N Diethylacetamide (23.6 mg, 0.0000975 mol), sodium tert-butoxide (9.37 mg, 0.0000975 mol), palladium acetate (0.44 mg, 0.0000020 mol) and 2- (di-tert-butylphosphino) ratio A mixture of phenyl (1.2 mg, 0.0000039 mol) was placed in a 10 mL round bottom flask equipped with a stir bar and reflux condenser and degassed and filled with nitrogen. 1,4-dioxane (0.65 mL, 0.0083 mol) was added to the mixture and the reaction mixture was refluxed overnight. After cooling, the mixture was filtered and the filtrate was adjusted to pH = 2.0 using TFA and purified by preparative HPLC to afford the desired product. LCMS: (M + H) ⁺ = 484.2.

Example 172

N-((3S) -1- {4-[(cyclopropylcarbonyl) (methyl) amino] phenyl} piperidin-3-yl) -4-hydroxyadamantane-1-carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 171, steps 1-4. LCMS: (M + H) ⁺ = 452.3.

Example 173

7-oxo-N-{(3S) -1- [4- (trifluoromethoxy) phenyl] piperidin-3-yl} azane-4-carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 171, steps 1-4. Two pure diastereomers were separated by preparative HPLC. LCMS: (M + H) ⁺ = 400.1.

Example 174

7-oxo-N-{(3S) -1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-3-yl} azane-4-carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 171, steps 1-4. Two pure diastereomers were separated by preparative HPLC. LCMS: (M + H) ⁺ = 385.2.

Example 175

7-oxo-N-[(3S) -1-phenylpiperidin-3-yl] azane-4-carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 171, steps 1-4. Two pure diastereomers were separated by preparative HPLC. LCMS: (M + H) ⁺ = 316.2.

Example 176

N-[(3S) -1- (2-fluoro-4-pyridin-4-ylphenyl) piperidin-3-yl] -4-hydroxyadamantane-1-carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 171, steps 1-4. LCMS: (M + H) ⁺ = 450.2.

Example 177

4-hydroxy-N-[(3S) -1- (1-naphthylsulfonyl) piperidin-3-yl] piperidine-1-carboxamide

Step 1. Tert-butyl (3S) -3-[(4-hydroxypiperidin-1-yl) carbonyl] aminopiperidine-1-carboxylate

This compound was prepared using a process similar to that described in Synthesis of Example 123, steps 3 and 4. LCMS: (M + H) ⁺ = 328.2; (M + H-Boc) ⁺ = 228.2.

Step 2. 4-hydroxy-N-[(3S) -1- (1-naphthylsulfonyl) piperidin-3-yl] piperidine-1-carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 9, steps 2 and 3. LCMS: (M + H) ⁺ = 418.1.

Example 178

N-{(3S) -1- [4- (difluoromethoxy) phenyl] piperidin-3-yl} -4-hydroxyadamantane-1-carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 171, steps 1-4. LCMS: (M + H) ⁺ = 421.2.

Example 179

N-{(3S) -1- [3-fluoro-5- (trifluoromethyl) phenyl] piperidin-3-yl} -4-hydroxyadamantane-1-carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 171, steps 1-4. LCMS: (M + H) ⁺ = 441.2.

Example 180

N-{(3S) -1- [3- (difluoromethoxy) phenyl] piperidin-3-yl} -4-hydroxyadamantane-1-carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 171, steps 1-4. LCMS: (M + H) ⁺ = 421.2.

Example 181

4-hydroxy-N-{(3S) -1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-3-yl} adamantane-1-carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 171, steps 1-4. LCMS: (M + H) ⁺ = 424.2.

Example 182

N-{(3S) -1- [3-chloro-5- (trifluoromethyl) pyridin-2-yl] piperidin-3-yl} -4-hydroxyadamantane-1-carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 171, steps 1-4. LCMS: (M + H) ⁺ = 458.1 / 460.1.

Example 183

4-hydroxy-N-{(3S) -1- [6-methyl-4- (trifluoromethyl) pyridin-2-yl] piperidin-3-yl} adamantane-1-carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 171, steps 1-4. LCMS: (M + H) ⁺ = 438.1.

Example 184

4-hydroxy-N-[(3S) -1- (6-methylpyridin-2-yl) piperidin-3-yl] adamantane-1-carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 171, steps 1-4. LCMS: (M + H) ⁺ = 370.2.

Example 185

N-[(3S) -1- (6-fluoropyridin-2-yl) piperidin-3-yl] -4-hydroxyadamantane-1-carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 171, steps 1-4. LCMS: (M + H) ⁺ = 374.1.

Example 186

4-hydroxy-N-[(3S) -1- (4-methylpyridin-2-yl) piperidin-3-yl] adamantane-1-carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 171, steps 1-4. LCMS: (M + H) ⁺ = 370.2.

Example 187

4-hydroxy-N-[(3S) -1- (4-methoxypyridin-2-yl) piperidin-3-yl] adamantane-1-carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 171, steps 1-4. LCMS: (M + H) ⁺ = 386.1.

Example 188

4-hydroxy-N-[(3S) -1- (6-methoxypyridin-2-yl) piperidin-3-yl] adamantane-1-carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 171, steps 1-4. LCMS: (M + H) ⁺ = 386.1.

Example 189

N-[(3S) -1- (5-fluoropyridin-2-yl) piperidin-3-yl] -4-hydroxyadamantane-1-carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 171, steps 1-4. LCMS: (M + H) ⁺ = 374.1.

Example 190

4-hydroxy-N-[(3S) -1- (5-methylpyridin-2-yl) piperidin-3-yl] adamantane-1-carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 171, steps 1-4. LCMS: (M + H) ⁺ = 370.1.

Example 191

N-[(3S) -1- (5-chloropyridin-2-yl) piperidin-3-yl] -4-hydroxyadamantane-1-carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 171, steps 1-4. LCMS: (M + H) ⁺ = 390.1 / 392.1.

Example 192

N-[(3S) -1- (2,5-difluoropyridin-3-yl) piperidin-3-yl] -4-hydroxyadamantane-1-carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 171, steps 1-4. LCMS: (M + H) ⁺ = 392.1.

Example 193

N-[(3S) -1- (3,5-difluoropyridin-2-yl) piperidin-3-yl] -4-hydroxyadamantane-1-carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 171, steps 1-4. LCMS: (M + H) ⁺ = 392.1.

Example 194

N-{(3S) -1- [4- (cyclohexyloxy) phenyl] piperidin-3-yl} -4-hydroxyadamantane-1-carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 171, steps 1-4. LCMS: (M + H) ⁺ = 453.2.

Example 195

N-{(3S) -1- [4- (cyclopentyloxy) phenyl] piperidin-3-yl} -4-hydroxyadamantane-1-carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 171, steps 1-4. LCMS: (M + H) ⁺ = 439.3.

Example 196

4-hydroxy-N-[(3S) -1-phenylpiperidin-3-yl] piperidine-1-carboxamide

Step 1. 4-hydroxy-N-[(3S) -piperidin-3-yl] piperidine-1-carboxamide hydrochloride

This compound was prepared using a process similar to that described in Synthesis of Example 163, steps 1 to 3. LCMS: (M + H) ⁺ = 228.2.

Step 2. 4-hydroxy-N-[(3S) -1-phenylpiperidin-3-yl] piperidine-1-carboxamide

Triethylamine (6.0E1 μL, 0.00043 mol) was added to 4-hydroxy-N-[(3S) -piperidin-3-yl] piperidine-1-ca in tetrahydrofuran (1.0 mL, 0.012 mol). To a mixture of voxamide hydrochloride (26.7 mg, 0.000101 mol), phenylboronic acid (35.7 mg, 0.000293 mol), cupric acetate (45.6 mg, 0.000251 mol) and 4A molecular sieve (99.3 mg, 0.000443 mol). . The resulting solution was stirred at rt for 7 h. The crude reaction mixture was purified directly by preparative HPLC to afford the desired product. LCMS: (M + H) ⁺ = 304.2.

Example 197

(1S, 5S) -3-hydroxy-N-[(3S) -1-phenylpiperidin-3-yl] -8-azabicyclo [3.2.1] octane-8-carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 196, Steps 1 and 2. LCMS: (M + H) ⁺ = 330.2.

Example 198

N-[(3S) -1- (3,4'-bipyridin-6-yl) piperidin-3-yl] -4-hydroxyadamantane-1-carboxamide

Sodium carbonate (10.6 mg, 0.000 100 mol) in water (0.10 mL) was added to N-[(3S) -1- (5-bromopyridin-2-yl) piperidin-3-yl]-in NMP (0.25 mL)- 4-hydroxyadamantane-1-carboxamide (21.7 mg, 0.0000500 mol, prepared using a process similar to that described in Examples 171, steps 1-4), toluene (100.0 μl, 0.0009388 mol) and To a mixture of 4-pyridinylboronic acid (7.38 mg, 0.0000600 mol) and tetrakis (triphenylphosphino) palladium (0) (1.7 mg, 0.0000015 mol) in ethanol (50.000 μL, 8.5633E-4 mol) was added. The organic layer was dried over Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The residue was dissolved in DMF and purified by preparative HPLC to afford the desired product. LCMS: (M + H) ⁺ = 433.2.

Example 199

N-((3S) -1- {5- [4- (acetylamino) phenyl] pyridin-2-yl} piperidin-3-yl) -4-hydroxyadamantane-1-carboxamide

This compound was prepared using a process similar to that described in the synthesis of Example 198. LCMS: (M + H) ⁺ = 489.3.

Example 200

N-{(3S) -1- [5- (4-cyanophenyl) pyridin-2-yl] piperidin-3-yl} -4-hydroxyadamantane-1-carboxamide

This compound was prepared using a process similar to that described in the synthesis of Example 198. LCMS: (M + H) ⁺ = 457.2.

Example 201

4-hydroxy-N-{(3S) -1- [4- (2-oxopyrrolidin-1-yl) phenyl] piperidin-3-yl} adamantane-1-carboxamide

Copper iodide (I) (0.95 g, 0.0050 mol), 2-pyrrolidinone (570 μl, 0.0075 mol), potassium carbonate (1.4 g, 0.010 mol), N-[(3S) -1- (4-bromo Phenyl) piperidin-3-yl] -4-hydroxyadamantane-1-carboxamide (0.4 g, 0.001 mol, prepared using a process similar to that described in Examples 1171, steps 1-4) And toluene (5.0 mL, 0.047 mol) was added to a 20 ml vial under nitrogen atmosphere. The reaction mixture was stirred at 110 ° C for 24 h. The reaction was purified by preparative HPLC to give the desired product. LCMS: (M + H) ⁺ = 439.2.

Example 202

4-hydroxy-N-{(3S) -1- [5- (4-methoxyphenyl) pyridin-2-yl] piperidin-3-yl} adamantane-1-carboxamide

This compound was prepared using a process similar to that described in the synthesis of Example 198. LCMS: (M + H) ⁺ = 462.3.

Example 203

Ethyl [4-((3S) -3-{[(4-hydroxy-1-adamantyl) carbonyl] amino} piperidin-1-yl) phenyl] methylcarbamate

This compound was prepared using a process similar to that described in the synthesis of Example 201. LCMS: (M + H) ⁺ = 456.3.

Example 204

N-[(3S) -1- (5- {4-[(cyclopropylamino) carbonyl] phenyl} pyridin-2-yl) piperidin-3-yl] -4-hydroxyadamantane-1 Carboxamide

This compound was prepared using a process similar to that described in the synthesis of Example 198. LCMS: (M + H) ⁺ = 515.3.

Example 205

N-[(3S) -1- (6'-fluoro-3,3'-bipyridin-6-yl) piperidin-3-yl] -4-hydroxyadamantane-1-carboxamide

This compound was prepared using a process similar to that described in the synthesis of Example 198. LCMS: (M + H) ⁺ = 451.3.

Example 206

Tert-butyl 4- [4-((3S) -3-{[(4-hydroxy-1-adamantyl) carbonyl] amino} piperidin-1-yl) phenoxy] piperidine- 1-carboxylate

This compound was prepared using a process similar to that described in Synthesis of Example 141, steps 1-4. LCMS: (M + H) ⁺ = 554.3.

Example 207

4-hydroxy-N-[(3S) -1- (6'-methoxy-3,3'-bipyridin-6-yl) piperidin-3-yl] adamantane-1-carboxamide

This compound was prepared using a process similar to that described in the synthesis of Example 198. LCMS: (M + H) ⁺ = 463.3.

Example 208

6 '-((3S) -3-{[(4-hydroxy-1-adamantyl) carbonyl] amino} piperidin-1-yl) -3,3'-bipyridine-6-carbox amides

This compound was prepared using a process similar to that described in the synthesis of Example 198. LCMS: (M + H) ⁺ = 476.2.

Example 209

4-hydroxy-N-[(3S) -1- (quinolin-8-ylsulfonyl) piperidin-3-yl] piperidine-1-carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 163, steps 1-4. LCMS: (M + H) ⁺ = 419.2.

Example 210

N-((3S) -1-{[5- (dimethylamino) -1-naphthyl] sulfonyl} piperidin-3-yl) -4-hydroxypiperidine-1-carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 163, steps 1-4. LCMS: (M + H) ⁺ = 461.2.

Example 211

(3-exo) -N-((3S) -1-{[5- (dimethylamino) -1-naphthyl] sulfonyl} piperidin-3-yl) -3-hydroxy-8-azabi Cyclo [3.2.1] octane-8-carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 163, steps 1-4. LCMS: (M + H) ⁺ = 487.3.

Example 212

(3-endo) -N-((3S) -1-{[5- (dimethylamino) -1-naphthyl] sulfonyl} piperidin-3-yl) -3-hydroxy-8-azabi Cyclo [3.2.1] octane-8-carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 163, steps 1-4. LCMS: (M + H) ⁺ = 487.3.

Example 213

3-hydroxy-N-[(3S) -1- (quinolin-8-ylsulfonyl) piperidin-3-yl] -8-azabicyclo [3.2.1] octane-8-carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 163, steps 1-4. LCMS: (M + H) ⁺ = 445.2.

Example 214

N-[(3S) -1- (2-fluorophenyl) piperidin-3-yl] -3-hydroxy-8-azabicyclo [3.2.1] octane-8-carboxamide

This compound was prepared using a process similar to that described in the synthesis of Example 196. LCMS: (M + H) ⁺ = 348.2.

Example 215

N-[(3S) -1- (4-fluorophenyl) piperidin-3-yl] -3-hydroxy-8-azabicyclo [3.2.1] octane-8-carboxamide

This compound was prepared using a process similar to that described in the synthesis of Example 196. LCMS: (M + H) ⁺ = 348.2.

Example 216

(3-endo) -N-[(3S) -1- (4-cyanophenyl) piperidin-3-yl] -3-hydroxy-8-azabicyclo [3.2.1] octane-8- Carboxamide

This compound was prepared using a process similar to that described in the synthesis of Example 196. LCMS: (M + H) ⁺ = 355.3.

Example 217

(3-endo) -3-hydroxy-N-{(3S) -1- [4- (methylsulfonyl) phenyl] piperidin-3-yl} -8-azabicyclo [3.2.1] octane -8-carboxamide

This compound was prepared using a process similar to that described in the synthesis of Example 196. LCMS: (M + H) ⁺ = 408.2.

Example 218

(3-endo) -3-hydroxy-N-{(3S) -1- [4- (trifluoromethoxy) phenyl] piperidin-3-yl} -8-azabicyclo [3.2.1] Octane-8-Carboxamide

This compound was prepared using a process similar to that described in the synthesis of Example 196. LCMS: (M + H) ⁺ = 414.2.

Example 219

N-{(3S) -1-[(4-chloro-1-naphthyl) sulfonyl] piperidin-3-yl} -4-hydroxypiperidine-1-carboxamide

This compound was prepared using a process analogous to that described in Example 123, steps 3 and 4, and then using a process similar to that described for synthesis of Example 9, steps 2 and 3. LCMS: (M + H) ⁺ = 452.2.

Example 220

N-[(3S) -1- (5-ethylpyrimidin-2-yl) piperidin-3-yl] -4-hydroxyadamantane-1-carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 141, steps 1-4. LCMS: (M + H) ⁺ = 385.3.

Example 221

4-hydroxy-N-{(3S) -1- [4- (trifluoromethyl) pyrimidin-2-yl] piperidin-3-yl} adamantane-1-carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 141, steps 1-4. LCMS: (M + H) ⁺ = 425.2.

Example 222

N-[(3S) -1- (2-chloropyrimidin-4-yl) piperidin-3-yl] -4-hydroxyadamantane-1-carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 141, steps 1-4. LCMS: (M + H) ⁺ = 391.2 / 393.2.

Example 223

N-[(3S) -1- (4-chloropyrimidin-2-yl) piperidin-3-yl] -4-hydroxyadamantane-1-carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 141, steps 1-4. LCMS: (M + H) ⁺ = 391.2 / 393.2.

Example 224

4-hydroxy-N-[(3S) -1- (4-pyridin-4-ylphenyl) piperidin-3-yl] adamantane-1-carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 171, steps 1-4. LCMS: (M + H) ⁺ = 432.3.

Example 225

N-{(3S) -1- [4- (3-fluoropyridin-4-yl) phenyl] piperidin-3-yl} -4-hydroxyadamantane-1-carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 171, steps 1-4. LCMS: (M + H) ⁺ = 450.3.

Example 226

4-hydroxy-N-[(3S) -1- (isoquinolin-5-ylsulfonyl) piperidin-3-yl] piperidine-1-carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 163, steps 1-4. LCMS: (M + H) ⁺ = 419.2.

Example 227

(3-endo) -3-hydroxy-N-[(3S) -1- (isoquinolin-5-ylsulfonyl) piperidin-3-yl] -8-azabicyclo [3.2.1] octane- 8-carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 163, steps 1-4. LCMS: (M + H) ⁺ = 445.2.

Example 228

(3-endo) -3-hydroxy-N-[(3S) -1- (2-naphthylsulfonyl) piperidin-3-yl] -8-azabicyclo [3.2.1] octane-8- Carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 163, steps 1-4. LCMS: (M + H) ⁺ = 444.2.

Example 229

(3-exo) -3-hydroxy-N-[(3S) -1- (2-naphthylsulfonyl) piperidin-3-yl] -8-azabicyclo [3.2.1] octane-8- Carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 163, steps 1-4. LCMS: (M + H) ⁺ = 444.2.

Example 230

(3-exo) -N-{(3S) -1-[(4-chloro-1-naphthyl) sulfonyl] piperidin-3-yl} -3-hydroxy-8-azabicyclo [3.2 .1] octane-8-carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 163, steps 1-4. LCMS: (M + H) ⁺ = 478.1 / 480.2.

Example 231

(3-endo) -N-{(3S) -1-[(4-chloro-1-naphthyl) sulfonyl] piperidin-3-yl} -3-hydroxy-8-azabicyclo [3.2 .1] octane-8-carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 163, steps 1-4. LCMS: (M + H) ⁺ = 478.1 / 480.2.

Example 232

4-hydroxy-N-[(3S) -1- (2-naphthylsulfonyl) piperidin-3-yl] piperidine-1-carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 163, steps 1-4. LCMS: (M + H) ⁺ = 418.2.

Example 233

N-[(3S) -1- (2,1,3-benzoxadiazol-4-ylsulfonyl) piperidin-3-yl] -4-hydroxypiperidine-1-carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 163, steps 1-4. LCMS: (M + H) ⁺ = 410.2.

Example 234

(3-endo) -N-[(3S) -1- (2,1,3-benzoxadiazol-4-ylsulfonyl) piperidin-3-yl] -3-hydroxy-8-azabi Cyclo [3.2.1] octane-8-carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 163, steps 1-4. LCMS: (M + H) ⁺ = 436.2.

Example 235

6-((3S) -3-{[(4-hydroxy-1-adamantyl) carbonyl] amino} piperidin-1-yl) -N, N-dimethylnicotinamide

4-hydroxy-N-[(3S) -piperidin-3-yl] adamantane-1-carboxamide (13.9 mg, 0.0000500 mol) in N, N-dimethylformamide (0.500 mL, 0.00646 mol) , Prepared using a process similar to that described in steps 1 to 3), 6-chloro-N, N-dimethylnicotinamide (13.8 mg, 0.0000750 mol) and N, N-diisopropyl The mixture of ethylamine (19.4 mg, 0.000150 mol) was irradiated with microwave at 120 ° C. for 10 minutes. The mixture was adjusted to pH = 2.0 using TFA and diluted with methanol (0.8 mL). The resulting solution was purified by preparative HPLC to give the desired product. LCMS: (M + H) ⁺ = 427.2.

Example 236

Tert-butyl 6-[(3S) -3-({[4- (acetyloxy) -1-adamantyl] carbonyl} amino) piperidin-1-yl] -3 ', 6'-di Hydro-3,4'-bipyridine-1 '(2'H) -carboxylate

This compound was prepared using a process similar to that described in the synthesis of Example 198. LCMS: (M + H) ⁺ = 579.3.

Example 237

Benzyl (3S) -3-{[(5-oxo-4-azatricyclo [4.3.1.1 (3,8)] undec-1-yl) carbonyl] amino} piperidine-1-carboxylate

Step 1. Benzyl (3S) -3-[(tert-butoxycarbonyl) amino] piperidine-1-carboxylate

This compound was prepared using a process similar to that described in Synthesis of Example 123, Step 1. LCMS: (M + H) ⁺ = 335.2.

Step 2. Benzyl (3S) -3-Aminopiperidine-1-carboxylate hydrochloride

This compound was prepared using a process similar to that described in Synthesis of Example 141, Step 3. LCMS: (M + H) ⁺ = 271.3.

Step 3. Benzyl (3S) -3-{[(4-oxo-1-adamantyl) carbonyl] amino} piperidine-1-carboxylate

This compound was prepared using a process similar to that described in Synthesis of Example 141, Step 1. LCMS: (M + H) ⁺ = 411.2.

Step 4. Benzyl (3S) -3-({[4- (hydroxyimino) -1-adamantyl] carbonyl} amino) piperidine-1-carboxylate

Benzyl (3S) -3-[(4-oxo-1-adamantyl) carbonyl] aminopiperidine-1-carboxylate (82.1 mg, 0.000200 mol) in methanol (1.0 mL) was dissolved in hydroxylamine (50.0). Μl, 0.000817 mol) and the mixture was stirred at rt overnight. The solvent was evaporated in vacuo to afford the desired product which was used directly in next step without further purification.

Step 5. Benzyl (3S) -3-{[(5-oxo-4-azatricyclo [4.3.1.1 (3,8)] undec-1-yl) carbonyl] amino} piperidine-1- Carboxylate

Benzyl (3S) -3-([4- (hydroxyimino) -1-adamantyl] carbonylamino) piperidine-1-carboxylate (0.083 g, 0.00020 mol) was concentrated in HCl at room temperature for 1 hour. (0.3 mL). The mixture was neutralized to pH = 3 with 1N NaOH and diluted with DMF (3.0 mL). The resulting mixture was purified by preparative HPLC to give the desired product. LCMS: (M + H) ⁺ = 426.2.

Example 238

(3-endo) -3-hydroxy-N-[(3S) -1- (4-nitrophenyl) piperidin-3-yl] -8-azabicyclo [3.2.1] octane-8-car Voxamide

Step 1: (3S) -1- (4-nitrophenyl) piperidin-3-amine

4-fluoronitrobenzene in a stirred solution of tert-butyl (3S) -piperidin-3-ylcarbamate (2.50 g, 0.0125 mol) in N, N-dimethylformamide (15.00 mL, 0.1937 mol) (2.29 g, 0.0162 mol) and potassium carbonate (2.59 g, 0.0187 mol) were added. After the reaction mixture was stirred at 90 ° C. for 13 hours, the reaction mixture was cooled to ambient temperature, the mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried and concentrated in vacuo and the resulting residue was used without further purification in the next step. LCMS (M + H) ⁺ 322.2. The crude material prepared previously was treated with 50 mL of TFA for 1 hour at room temperature. The volatiles were removed in vacuo and the residue diluted with methylene chloride and washed with 1N NaOH. The organic layers were combined, washed with water and brine, dried and evaporated to dryness. LCMS (M + H) ⁺ 222.2.

Step 2: (3-endo) -3-hydroxy-N-[(3S) -1- (4-nitrophenyl) piperidin-3-yl] -8-azabicyclo [3.2.1] octane- 8-carboxamide

The title compound was prepared using a process similar to that described in Synthesis of Example 123, steps 3 and 4. LCMS: (M + H) ⁺ = 375.2.

Example 239

N-((3S) -1-4-[(1-acetylpiperidin-4-yl) oxy] phenylpiperidin-3-yl) -4-hydroxyadamantane-1-carboxamide

Title compound is 4-hydroxy-N-[(3S) -piperidin-3-yl] adamantane-1-carboxamide and tert-butyl 4- (4-chlorophenoxy) piperidine- Synthesis of Example 171 starting from 1-carboxylate, prepared using a process similar to that described in steps 1 to 4, which is subsequently deprotected using the protocol outlined in Example 1, step 2 and It was a true story. LCMS: (M + H) ⁺ = 496.3.

Example 240

Methyl 4- [4-((3S) -3-{[(4-hydroxy-1-adamantyl) carbonyl] amino} piperidin-1-yl) phenoxy] piperidine-1-carboxyl Rate

The title compound was prepared using a process similar to that described in the synthesis of Example 239. LCMS: (M + H) ⁺ = 512.3.

Example 241

4-hydroxy-N-[(3S) -1- (4-{[1- (methylsulfonyl) piperidin-4-yl] oxy} phenyl) piperidin-3-yl] adamantane- 1-carboxamide

The title compound was prepared using a process similar to that described in the synthesis of Example 239. LCMS: (M + H) ⁺ = 532.3.

Example 242

N-((3S) -1- {4- [acetyl (methyl) amino] phenyl} piperidin-3-yl) -4-hydroxyadamantane-1-carboxamide

The title compound was prepared using a process similar to that described in Synthesis of Examples 171, steps 1-4. LCMS: (M + H) ⁺ = 426.3.

Example 243

(3-endo) -N-[(3S) -1- (4-aminophenyl) piperidin-3-yl] -3-hydroxy-8-azabicyclo [3.2.1] octane-8-car Voxamide

(3-endo) -3-hydroxy-N-[(3S) -1- (4-nitrophenyl) piperidin-3-yl] -8-azabicyclo [3.2.1] octane in 50 mL MeOH A mixture of 8-carboxamide (1.86 g, 0.00497 mol, prepared as in Example 238) was hydrogenated overnight in the presence of 10% Pd / C under a hydrogen pressure balloon. The catalyst was filtered off and the filtrate was concentrated in vacuo. LCMS: (M + H) ⁺ = 345.3.

Example 244

(3-endo) -3-hydroxy-N-((3S) -1- {4-[(methylsulfonyl) amino] phenyl} piperidin-3-yl) -8-azabicyclo [3.2. 1] octane-8-carboxamide

(3-endo) -N-[(3S) -1- (4-aminophenyl) piperidin-3-yl] -3-hydroxy-8-azabicyclo in methylene chloride (0.30 mL, 0.0047 mol) [3.2.1] methanesulfonyl chloride (0.00843) in a mixture of octane-8-carboxamide (30.0 mg, 0.0000871 mol, prepared as in Example 243) and 4-dimethylaminopyridine (16.0 mg, 0.000131 mol) mL, 0.000109 mol) was added. The mixture was stirred at rt for 1 h. After the volatiles were removed in vacuo, the residue was diluted with water and ACN and purified on RP-HPLC to give the product. LCMS (M + H) ⁺ 423.2.

Example 245

Ethyl {4-[(3S) -3-({[(3-endo) -3-hydroxy-8-azabicyclo [3.2.1] oct-8-yl] carbonyl} amino) piperidine- 1-yl] phenyl carbamate

(3-endo) -N-[(3S) -1- (4-aminophenyl) piperidin-3-yl] -3-hydroxy-8-azabicyclo in methylene chloride (0.30 mL, 0.0047 mol) [3.2.1] 1.0 M sodium hydroxide in water (0.1306 mL) was added to a mixture of octane-8-carboxamide (30.0 mg, 0.0000871 mol, prepared as in Example 243), followed by ethyl chloroformate. (0.0104 mL, 0.000109 mol) was added. The reaction was stirred at rt for 1 h. After the volatiles were removed in vacuo, the residue was neutralized using diluted TFA and purified on RP-HPLC to give the desired product. LCMS (M + H) 417.3.

Example 246

(3-endo) -3-hydroxy-N-{(3S) -1- [4- (2-oxopiperidin-1-yl) phenyl] piperidin-3-yl} -8-azabi Cyclo [3.2.1] octane-8-carboxamide

(3-endo) -N-[(3S) -1- (4-aminophenyl) piperidin-3-yl] -3-hydroxy-8-azabi in tetrahydrofuran (0.80 mL, 0.0099 mol) 5-bromovaleric in a mixture of cyclo [3.2.1] octane-8-carboxamide (30.0 mg, 0.0000871 mol, prepared as in Example 243) and 4-dimethylaminopyridine (15.96 mg, 0.0001306 mol) Chloride (0.0146 mL, 0.000109 mol) was added. The reaction was stirred at rt for 1 h to afford acylated product, which was detected as LCMS (M + H) ⁺ 507.2. To the reaction mixture was added 1.0 M potassium tert-butoxide in tetrahydrofuran (0.261 mL). After stirring for 2 hours, the volatiles were removed in vacuo and the residue was neutralized using diluted TFA and purified on RP-HPLC to give the desired product. LCMS (M + H) ⁺ 427.3.

Example 247

N-{(3S) -1- [4- (acetylamino) phenyl] piperidin-3-yl} -4-hydroxyadamantane-1-carboxamide

The title compound was prepared using a process similar to that described in Synthesis of Examples 171, steps 1-4. LCMS: (M + H) ⁺ = 412.2.

Example 248

N-{(3S) -1- [4- (acetylamino) phenyl] piperidin-3-yl} -4-oxoadamantane-1-carboxamide

The title compound was prepared using a process similar to that described in Synthesis of Example 171, steps 1, 3-4. LCMS: (M + H) ⁺ = 410.2.

Example 249

N-((3S) -1- {4-[(cyclopropylcarbonyl) amino] phenyl} piperidin-3-yl) -4-hydroxyadamantane-1-carboxamide

The title compound was prepared using a process similar to that described in Synthesis of Examples 171, steps 1-4. LCMS: (M + H) ⁺ = 438.3.

Example 250

4-hydroxy-4-methyl-N-{(3S) -1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-3-yl} adamantane-1-carboxamide

Step 1: benzyl (3S) -3-{[(4-hydroxy-4-methyl-1-adamantyl) carbonyl] amino} piperidine-1-carboxylate

Benzyl (3S) -3-{[(4-oxo-1-adamantyl) carbonyl] amino} piperidine-1-carboxylate (41.0 mg, 0.0000999 mol, in Example 171 in THF (2.0 mL) Prepared as the product from step 1 in the synthesis) was cooled to -78 ° C using a dry ice bath. Methyllithium (0.15 mL, 0.0050 mol) was added to the cooled solution. After stirring for 30 minutes, the reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was dried over Na ₂ S0 ₄ , filtered and concentrated under reduced pressure.

Step 2: 4-hydroxy-4-methyl-N-[(3S) -piperidin-3-yl] adamantane-1-carboxamide

This compound was prepared using a process similar to that described in Synthesis of Example 171, Step 3. LCMS: (M + H) ⁺ = 293.3.

Step 3: 4-hydroxy-4-methyl-N-{(3S) -1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-3-yl} adamantane-1- Carboxamide

4-hydroxy-4-methyl-N-[(3S) -piperidin-3-yl] adamantane-1-carboxamide (20.6 in N, N-dimethylformamide (0.705 mL, 0.00911 mol) mg, 0.0000704mol), 20 at 150 ° C. in a mixture of 2-chloro-5- (trifluoromethyl) pyridine (19.2mg, 0.000106mol) and N, N-diisopropylethylamine (35 uL, 0.00020mol) Microaves were examined for minutes. The mixture was adjusted to pH = 2.0 with TFA and diluted with methanol (0.8 mL). The resulting solution was purified by preparative HPLC to give the desired product. LCMS: (M + H) ⁺ = 438.3.

Example 251

Methyl [4-((3S) -3-{[(4-hydroxy-1-adamantyl) carbonyl] amino} piperidin-1-yl) phenyl] carbamate

The title compound was prepared using a process similar to that described in Synthesis of Examples 171, steps 1-4. LCMS: (M + H) ⁺ = 428.3.

Example 252

(3-endo) -3-hydroxy-N-{(3S) -1- [4- (trifluoromethyl) phenyl] piperidin-3-yl} -8-azabicyclo [3.2.1] Octane-8-Carboxamide

The title compound was prepared using a process similar to that described in Synthesis of Example 196, Steps 1 and 2. LCMS: (M + H) ⁺ = 398.2.

Example 253

(3-endo) -N-[(3S) -1-biphenyl-4-ylpiperidin-3-yl] -3-hydroxy-8-azabicyclo [3.2.1] octane-8-carbox amides

The title compound was prepared using a process similar to that described in Synthesis of Example 196, Steps 1 and 2. LCMS: (M + H) ⁺ = 406.3.

Example 254

(3-endo) -N-((3S) -1- {4-[(cyclopropylacetyl) amino] phenyl} piperidin-3-yl) -3-hydroxy-8-azabicyclo [3.2. 1] octane-8-carboxamide

(3-endo) -N-[(3S) -1- (4-aminophenyl) piperidin-3-yl] -3-hydroxy- in N, N-dimethylformamide (0.30 mL, 0.0039 mol) Benzotriazole in a mixture of 8-azabicyclo [3.2.1] octane-8-carboxamide (30.0 mg, 0.0000871 mol, prepared as in Example 243) and cyclopropaneacetic acid (10.9 mg, 0.000109 mol) -1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (57.8 mg, 0.000131 mol) was added. After stirring for 10 minutes at room temperature, N, N-diisopropylethylamine (0.0303 mL, 0.000174 mol) was added and the reaction mixture was stirred for an additional 1 hour at room temperature. The crude mixture was diluted with ACN and water and purified on RP-HPLC to give the desired product. LCMS (M + H) ⁺ 427.3.

Example 255

(3-endo) -3-hydroxy-N-{(3S) -1- [4- (2-oxopyrrolidin-1-yl) phenyl] piperidin-3-yl} -8-azabi Cyclo [3.2.1] octane-8-carboxamide

(3-endo) -N-[(3S) -1- (4-aminophenyl) piperidin-3-yl] -3-hydroxy-8-azabi in tetrahydrofuran (0.80 mL, 0.0099 mol) 4-bromobutanoyl in a mixture of cyclo [3.2.1] octane-8-carboxamide (30.0 mg, 0.0000871 mol, prepared as in Example 243) and 4-dimethylaminopyridine (15.96 mg, 0.0001306 mol) Chloride (0.0126 mL, 0.000109 mol) was added. The reaction mixture was stirred at rt for 1 h, then 1.0 M potassium tert-butoxide in tetrahydrofuran (0.348 mL) was added and stirring continued at rt for 2 h. The volatiles were removed in vacuo and the residue was neutralized with diluted TFA and purified on RP-HPLC to give the product. LCMS (M + H) ⁺ 427.3.

Example 256

(3-endo) -3-hydroxy-N-{(3S) -1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-3-yl} -8-azabicyclo [ 3.2.1] octane-8-carboxamide

(3-endo) -3-hydroxy-N-[(3S) -piperidin-3-yl] -8-azabicyclo [3.2.1 in N-methylpyrrolidinone (0.75 mL, 0.0078 mol) ] Octane-8-carboxamide hydrochloride (15.3 mg, 0.0000528 mol; prepared as in Example 163, steps 1-3), N, N-diisopropylethylamine (55 μL, 0.00032 mol) and 2 A mixture of -chloro-5- (trifluoromethyl) pyridine (15.0 mg, 0.0000826 mol) was irradiated with microwave at 150 ° C. for 15 minutes. LCMS (M + H) ⁺ 399.2.

Example 257

(3-endo) -N-[(3S) -1- (6-fluoropyridin-2-yl) piperidin-3-yl] -3-hydroxy-8-azabicyclo [3.2.1] Octane-8-Carboxamide

The title compound was prepared using a process similar to that described in the synthesis of Example 256. LCMS: (M + H) ⁺ = 349.3.

Example A

Enzyme Assay of 11βHSD1

All in vitro assays were performed with clear lysate as a source of 11βHSD1 activity. HEK-293 transient transfectants expressing epitope-tagged versions of the full-length human 11βHSD1 were harvested by centrifugation. About 2 × 10 ⁷ cells were resuspended in 40 mL of lysis buffer (25 mM Tris-HCl, pH 7.5, 0.1 M NaCl, 1 mM MgCl ₂ and 250 mM sucrose) and lysed in a microfluidizer. The lysate was purified by centrifugation, the supernatant was aliquoted and frozen.

Inhibition of 11βHSD1 by the test compound was assayed in vitro by the Scintillation Proximity Assay (SPA). It was diluted in DMSO to a concentration suitable for the SPA assay. Two-fold serial dilutions of 0.8 μl of compound were spotted onto 384 well plates in DMSO to reach 3 log of compound concentration. 20 μl of purified lysate was added to each well. Reaction was performed with 20 μl of substrate-cofactor mixture in assay buffer (25 mM Tris-HCl, pH 7.5, 0.1 M NaCl, 1 mM MgCl ₂ ) to a final concentration of 400 μM NADPH, 25 nM ³ H-cortisone and 0.007% Triton X-100. In addition, it started. The plate was incubated at 37 ° C. for 1 hour. The reaction was quenched by adding 40 μl of anti-mouse coated SPA beads preincubated with 10 μM carbenoxolone and cortisol-specific monoclonal antibodies. The quenched plates were incubated for at least 30 minutes at room temperature before reading with a Topcount scintillation counter. Controls without lysate, controls with inhibited lysate and controls without mAb were routinely performed. About 30% of the input cortisone is reduced by 11βHSD1 in non-suppressed reactions under these conditions.

According to this assay a test compound with an IC ₅₀ value of less than about 20 μM was considered active.

Example B

Cell-Based Assays for HSD Activity

Peripheral blood mononuclear cells (PBMCs) were isolated from normal human volunteers by Ficoll density centrifugation. Cells were plated in 96 well plates in 200 μl of AIM V (Gibco-BRL) medium in ⁴ × 10 ⁵ cells / well. Cells were stimulated overnight with 50ng / mL recombinant IL-4 (R & D Systems). The next morning, 200 nM Cortisone (Sigma) was added in the presence or absence of various concentrations of compound. Cells were incubated for 48 hours and supernatants were obtained. The conversion from cortisone to cortisol was measured by commercial ELISA (Assay Design).

According to this assay a test compound with an IC ₅₀ value of less than about 20 μM was considered active.

Example C

Cell assays to assess MR antagonism

Assays for MR antagonism were performed essentially as described in Jausons-Loffreda et al. J Biolumin and Chemilumin, 1994, 9: 217-221. Briefly, HEK293 / MSR cells (Invitrogen Corp.) were co-transfected with three plasmids: 1) plasmid designed to express a fusion protein of the GAL4 DNA binding domain and the mineralocorticoid receptor ligand binding domain, 2) Plasmids containing the GAL4 upstream activation sequence located upstream of the firefly luciferase receptor gene (pFR-LUC, Stratagene, Inc.) and 3) Renilla cloned downstream of the thymidine kinase promoter (Promega). A plasmid comprising the luciferase receptor gene. Transfection was performed using FuGENE6 reagent (Roche). The transfected cells were prepared for use in subsequent assays 24 hours after transfection.

To assess the ability of a compound to antagonize MR, test compounds are diluted in cell culture medium supplemented with 1 nM aldosterone (E-MEM, 10% charcoal-striped FBS, 2 mM L-glutamine) and for 16-18 hours. It was applied to the transfected cells. After incubating the cells with the test compound and aldosterone, the activity of firefly luciferase (indicator of MR antagonism by aldosterone) and Renilla luciferase (normalization control) were used using the dual-glo luciferase assay system (Promega) It was measured by. Antagonism of the mineralocorticoid receptor was monitored for the ability of the test compound to attenuate aldosterone-induced firefly luciferase activity. Measured.

Test compounds with IC ₅₀ values of less than 100 μM were considered active.

In addition to those described herein, various modifications of the invention are apparent to those skilled in the art from the above description. Such modifications are also intended to fall within the scope of the appended claims. Each reference, including all patent applications and publications cited herein, is incorporated herein by reference in its entirety.

Claims (55)

A compound of formula (Ia) or a pharmaceutically acceptable salt or prodrug thereof. Formula Ia

In Formula Ia, L is absent or S (O) ₂ , S (O), S, C (O), C (O) O, C (O) O- (C _1-3 alkylene) or C (O) NR ^L ego; Ar is aryl or heteroaryl, optionally substituted by 1, 2, 3, 4 or 5 W-X-Y-Z, respectively; R ^L is H or C _1-6 alkyl; R ¹ is H, C (O) OR ^{b '} , S (O) R ^a' , S (O) NR ^{c '} R ^d' , S (O) ₂ R ^{a '} , S (O) ₂ NR ^c' R ^{d '} , C _1-10 alkyl, C _1-10 haloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cyclo Alkylalkyl or heterocycloalkylalkyl, wherein C _1-10 alkyl, C _1-10 haloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclo Alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 or 3 R ¹⁴ ; R ² is each H, C _1-6 alkyl, arylalkyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl, optionally substituted by 1, 2 or 3 R ¹⁴ ; R ³ is each H, C _1-6 alkyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl optionally substituted by 1, 2 or 3 W′-X′-Y′-Z ′; R ³ is NR ^3a R ^3b ; R ^3a and R ^3b are each independently H, C _1-6 alkyl, aryl, cycloalkyl, heteroaryl or hetero optionally substituted by 1, 2 or 3 W'-X'-Y'-Z ', respectively Cycloalkyl; R ^3a and R ^3b together with the N atom to which they are attached form a 4-14 membered heterocycloalkyl group optionally substituted by 1, 2 or 3 W'-X'-Y'-Z '; R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each independently H, OC (O) R ^{a '} , OC (O) OR ^b' , C (O) OR ^{b '} , OC (O) NR ^c' R ^{d '} , NR ^c' R ^{d '} , NR ^c' C (O) R ^{a '} , NR ^c' C (O) OR ^{b '} , S (O) R ^a' , S (O) NR ^{c '} R ^d' , S (O) ₂ R ^{a '} , S (O) ₂ NR ^c' R ^{d '} , SR ^b' , C _1-10 alkyl, C _1-10 haloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C _1-10 alkyl , C _1-10 haloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl Optionally substituted by 1, 2 or 3 R ¹⁴ ; or R ¹ and R ² together with the carbon and nitrogen atoms to which they are attached form a 3 to 14 membered heterocycloalkyl group optionally substituted by 1, 2 or 3 R ¹⁴ ; R ¹ and R ³ together with the carbon atom to which they are attached and the intervening —NR ² CO— moiety form a 4 to 14 membered heterocycloalkyl group optionally substituted by 1, 2 or 3 R ¹⁴ ; R ² and R ³ together with the carbon and nitrogen atoms to which they are attached form a 3 to 14 membered heterocycloalkyl group optionally substituted by 1, 2 or 3 R ¹⁴ ; R ⁴ and R ⁵ together with the carbon atom to which they are attached form a 3- to 14-membered cycloalkyl or heterocycloalkyl group optionally substituted by 1, 2 or 3 R ¹⁴ ; Or R ⁶ and R ⁷ together with the carbon atom to which they are attached form a 3 to 14 membered cycloalkyl or heterocycloalkyl group optionally substituted by 1, 2 or 3 R ¹⁴ ; R ⁸ and R ⁹ together with the carbon atom to which they are attached form a 3- to 14-membered cycloalkyl or heterocycloalkyl group optionally substituted by 1, 2 or 3 R ¹⁴ ; R ¹⁰ and R ¹¹ together with the carbon atom to which they are attached form a 3- to 14-membered cycloalkyl or heterocycloalkyl group optionally substituted by 1, 2 or 3 R ¹⁴ ; R ⁴ and R ⁶ together with the carbon atom to which they are attached are a 3-7 membered fused cycloalkyl group or 3-7 membered fused heterocyclo optionally substituted by 1, 2 or 3 R ¹⁴ To form an alkyl group; R ⁶ and R ⁸ together with the carbon atom to which they are attached are a 3-7 membered fused cycloalkyl group or 3-7 membered fused heterocyclo optionally substituted by 1, 2 or 3 R ¹⁴ To form an alkyl group; R ¹⁴ is halo, C _1-4 alkyl, C _1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO ₂ , OR ^{a '} , SR ^a' , C (O) R ^{b '} , C (O) NR ^{c '} R ^d' , C (O) OR ^{a '} , OC (O) R ^b' , OC (O) NR ^{c '} R ^d' , NR ^{c '} R ^d' , NR ^{c '} C (O) R ^{d '} , NR ^c' C (O) OR ^{a '} , S (O) R ^b' , S (O) NR ^{c '} R ^d' , S (O) ₂ R ^{b '} or S (O) ₂ NR ^{c '} R ^d' ; W, W 'and W "are each independently absent or C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynylenyl, O, S, NR ^e , CO, COO, CONR ^e , SO, SO ₂ , SONR ^e or NR ^e CONR ^f , wherein C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynylenyl are each 1, 2 or 3 halo, Optionally substituted by OH, C _1-4 alkoxy, C _1-4 haloalkoxy, amino, C _1-4 alkylamino or C _2-8 dialkylamino; X, X 'and X "are each independently absent or C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynenyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl Wherein C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynylenyl, cycloalkyl, heteroaryl or heterocycloalkyl is one or more halo, CN, NO ₂ , OH, C _1- Optionally substituted by ₄ alkoxy, C _1-4 haloalkoxy, amino, C _1-4 alkylamino or C _2-8 dialkylamino; Y, Y 'and Y "are each independently, absent or C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynylenyl, O, S, NR ^e , CO, COO, CONR ^e , SO, SO ₂ , SONR ^e or NR ^e CONR ^f , wherein C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynylenyl are each 1, 2 or 3 halo, Optionally substituted by OH, C _1-4 alkoxy, C _1-4 haloalkoxy, amino, C _1-4 alkylamino or C _2-8 dialkylamino; Z, Z 'and Z "are each independently H, halo, CN, NO ₂ , OH, C _1-4 alkoxy, C _1-4 haloalkoxy, amino, C _1-4 alkylamino or C _2-8 dialkyl Amino, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl may be 1, 2 or 3 halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{1- 4} haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO ₂ , OR ^a , SR ^a , C (O) R ^b , C (O) NR ^c R ^d , C (O) OR ^a , OC (O) R ^b , OC (O) NR ^c R ^d , NR ^c R ^d , NR ^c C (O) R ^d , NR ^c C (O) OR ^a , S (O) R ^b , S (O) Optionally substituted by NR ^c R ^d , S (O) ₂ R ^b or S (O) ₂ NR ^c R ^d , Wherein two -WXYZs bonded to the same atom each represent a 3-14 membered cycloalkyl or heterocycloalkyl group optionally substituted by 1, 2 or 3 -W "-X" -Y "-Z" Optionally form; Wherein two -W'-X'-Y'-Z's bonded to the same atom are each three to fourteen, optionally substituted by one, two or three -W "-X" -Y "-Z"; Optionally forms a cycloalkyl or heterocycloalkyl group; Wherein -W-X-Y-Z is not H; Wherein -W'-X'-Y'-Z 'is not H; Wherein -W "-X" -Y "-Z" is not H; R ^a and R ^{a '} are each independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocyclo Alkyl, wherein C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl; Heterocycloalkyl, heterocycloalkylalkyl is selected from H, OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl Optionally substituted; R ^b and R ^{b ′} are each independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl , Arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cyclo Alkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is H, OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _{1 -Optionally} substituted by haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; R ^c and R ^d are each independently H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl , Arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, hetero Aryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is H, OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 Optionally substituted by haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or R ^c and R ^d together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group; R ^{c '} and R ^d' are each independently H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclo Alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, Heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is H, OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1- Optionally substituted by ₆ haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or R ^{c '} and R ^d' together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group; R ^e and R ^f are each independently H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, Arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl , Cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is H, OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 halo Optionally substituted by alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or R ^e and R ^f together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group; q is 1 or 2, only, (a) when L is absent and R ² is methyl, then R ³ is not C _2-3 alkyl substituted by S (O) ₂ R ^b ; (b) when L is absent and R ³ is methyl, then R ² is not ethyl substituted by NR ^{c ′} R ^{d ′} ; (c) when L is S (O) ₂ and Ar is 4-methylphenyl, then R ³ is not piperazin-1-yl 4-substituted by aryl; (d) when L is S (O) ₂ and q is 2, Ar is not aryl optionally substituted by 1, 2, 3, 4 or 5 WXYZ; (e) when L is C (O) NH and Ar is phenyl substituted by COOH, R ³ is heteroaryl substituted by two W'-X'-Y'-Z 'or two W'- Not ethyl substituted by X'-Y'-Z '; (f) R ³ is not piperidin-3-yl N-substituted with one C (O)-(C _1-4 alkyl) or one C (O) O (C _1-4 alkyl) . The compound of claim 1, wherein L is S (O) ₂ . The compound of claim 1, wherein L is absent. The compound of claim 1, wherein L is C (O). The compound of claim 1, wherein L is C (O) NR ^L. The compound of claim 1, wherein L is C (O) O— (C _1-3 alkylene). The compound of formula IIa according to claim 1. Formula IIa

8. A compound according to claim 7, wherein Ar is phenyl, pyridyl, pyrimidinyl or thiazolyl, each optionally substituted by 1 or 2 W-X-Y-Z. 8. The compound of claim 7, wherein Ar is 1 or 2 halo, nitro, cyano, amino, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, dialkyl Aminocarbonyl, dialkylaminocarbonylalkyloxy, cycloalkylcarbonylamino, cycloalkylcarbonyl (alkyl) amino, alkoxycarbonylamino, alkoxycarbonyl, alkylsulfonyl, alkylsulfonylamino, cycloalkylalkylcarbonyl Amino, aryl, heteroaryl, heterocycloalkyl, arylalkyloxy, cycloalkyloxy, heterocycloalkyloxy, acylamino, acyl (alkyl) amino; 1,2,3,6-tetrahydropyridinyl substituted by alkoxycarbonyl; Phenyl, pyridyl, pyrimidinyl or thiazolyl optionally substituted by 2-oxopiperidinyl or 2-oxopyrrolidinyl, wherein aryl, heteroaryl, heterocycloalkyl and heterocycloalkyloxy are each one or more A compound optionally substituted by halo, cyano, C _1-4 alkoxy, acyl, acylamino, alkylsulfonyl, cycloalkylaminocarbonyl, alkoxycarbonyl or aminocarbonyl. 8. Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, bi, according to claim 7, wherein R ³ is each optionally substituted with one or two W'-X'-Y'-Z '. Cyclo [3.2.1] octanyl, norbornyl, 1,2,3,4-tetrahydronaphthyl, azepan-7-one-yl, 8-aza-bicyclo [3.2.1] octanyl, indole Compound which is reyl, quinolinyl, indol-3-ylmethyl or phenyl. 8. The compound of claim 7, wherein R ³ is 1 or 2 halo, OH, C _1-4 alkyl, C _1-4 alkoxy, hydroxylalkyl, aryl, aryloxy, heteroaryl, heteroarylalkyl or alkylcarbonyloxy Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, bicyclo [3.2.1] octanyl, norbornyl, 1,2,3,4-tetrahydronaphthyl optionally substituted by , Azepan-7-on-yl, 8-aza-bicyclo [3.2.1] octanyl or phenyl, wherein aryl, heteroaryl, heteroarylalkyl is one or two optionally substituted by alkoxycarbonyl A compound optionally substituted by C _1-4 alkyl or heterocycloalkyl. The compound of formula IIIa according to claim 1. Formula IIIa

The compound of formula IVa according to claim 1. Formula IVa

The compound of formula Va according to claim 1. Chemical formula Va

A compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof. Formula I

In Formula I, Ar is aryl or heteroaryl, optionally substituted by 1, 2, 3, 4 or 5 W-X-Y-Z, respectively; R ¹ is H, C (O) OR ^{b '} , S (O) R ^a' , S (O) NR ^{c '} R ^d' , S (O) ₂ R ^{a '} , S (O) ₂ NR ^c' R ^{d '} , C _1-10 alkyl, C _1-10 haloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cyclo Alkylalkyl or heterocycloalkylalkyl, wherein C _1-10 alkyl, C _1-10 haloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, Arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 or 3 R ¹⁴ ; R ² is each H, C _1-6 alkyl, arylalkyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl or heterocycloalkylalkyl, optionally substituted by 1, 2 or 3 R ¹⁴ ; R ³ is each H, C _1-6 alkyl, aryl, cycloalkyl or heteroaryl, optionally substituted by 1, 2 or 3 W'-X'-Y'-Z '; R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each independently H, OC (O) R ^{a '} , OC (O) OR ^b' , C (O) OR ^{b '} , OC (O) NR ^c' R ^{d '} , NR ^c' R ^{d '} , NR ^c' C (O) R ^{a '} , NR ^c' C (O) OR ^{b '} , S (O) R ^a' , S (O) NR ^{c '} R ^d' , S (O) ₂ R ^{a '} , S (O) ₂ NR ^c' R ^{d '} , SR ^b' , C _1-10 alkyl, C _1-10 haloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C _1-10 Alkyl, C _1-10 haloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl Is optionally substituted by 1, 2 or 3 R ¹⁴ ; or R ¹ and R ² together with the carbon and nitrogen atoms to which they are attached form a 3 to 14 membered heterocycloalkyl group optionally substituted by 1, 2 or 3 R ¹⁴ ; R ¹ and R ³ together with the carbon atom to which they are attached and the intervening —NR ² CO— moiety form a 4 to 14 membered heterocycloalkyl group optionally substituted by 1, 2 or 3 R ¹⁴ ; R ² and R ³ together with the carbon and nitrogen atoms to which they are attached form a 3 to 14 membered heterocycloalkyl group optionally substituted by 1, 2 or 3 R ¹⁴ ; R ⁴ and R ⁵ together with the carbon atom to which they are attached form a 3 to 14 membered cycloalkyl or 3 to 14 membered heterocycloalkyl group optionally substituted by 1, 2 or 3 R ¹⁴ ; R ⁶ and R ⁷ together with the carbon atom to which they are attached form a 3 to 14 membered cycloalkyl or 3 to 14 membered heterocycloalkyl group optionally substituted by 1, 2 or 3 R ¹⁴ ; R ⁸ and R ⁹ together with the carbon atom to which they are attached form a 3 to 14 membered cycloalkyl or 3 to 14 membered heterocycloalkyl group optionally substituted by 1, 2 or 3 R ¹⁴ ; R ¹⁰ and R ¹¹ together with the carbon atom to which they are attached form a 3 to 14 membered cycloalkyl or 3 to 14 membered heterocycloalkyl group optionally substituted by 1, 2 or 3 R ¹⁴ ; R ⁴ and R ⁶ together with the carbon atom to which they are attached are a 3-7 membered fused cycloalkyl group or 3-7 membered fused heterocyclo optionally substituted by 1, 2 or 3 R ¹⁴ To form an alkyl group; R ⁶ and R ⁸ together with the carbon atom to which they are attached are a 3-7 membered fused cycloalkyl group or a 3-7 membered fused heterocyclo optionally substituted by 1, 2 or 3 R ¹⁴ To form an alkyl group; R ¹⁴ is halo, C _1-4 alkyl, C _1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO ₂ , OR ^{a '} , SR ^a' , C (O) R ^{b '} , C (O) NR ^{c '} R ^d' , C (O) OR ^{a '} , OC (O) R ^b' , OC (O) NR ^{c '} R ^d' , NR ^{c '} R ^d' , NR ^{c '} C (O) R ^{d '} , NR ^c' C (O) OR ^{a '} , S (O) R ^b' , S (O) NR ^{c '} R ^d' , S (O) ₂ R ^{b '} or S (O) ₂ NR ^{c '} R ^d' ; W, W 'and W "are each independently absent or C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynylenyl, O, S, NR ^e , CO, COO, CONR ^e , SO, SO ₂ , SONR ^e or NR ^e CONR ^f , wherein C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynylenyl are 1, 2 or 3 halo, OH Optionally substituted by C _1-4 alkoxy, C _1-4 haloalkoxy, amino, C _1-4 alkylamino or C _2-8 dialkylamino; X, X 'and X "are each independently absent or C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynenyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl Wherein C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynylenyl, cycloalkyl, heteroaryl or heterocycloalkyl is one or more halo, CN, NO ₂ , OH, C _1- Optionally substituted by ₄ alkoxy, C _1-4 haloalkoxy, amino, C _1-4 alkylamino or C _2-8 dialkylamino; Y, Y 'and Y "are each independently absent or C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynylenyl, O, S, NR ^e , CO, COO, CONR ^e , SO, SO ₂ , SONR ^e or NR ^e CONR ^f , wherein C _1-6 alkylenyl, C _2-6 alkenylenyl, C _2-6 alkynylenyl are each 1, 2 or 3 halo, OH Optionally substituted by C _1-4 alkoxy, C _1-4 haloalkoxy, amino, C _1-4 alkylamino or C _2-8 dialkylamino; Z, Z 'and Z "are each independently H, halo, CN, NO ₂ , OH, C _1-4 alkoxy, C _1-4 haloalkoxy, amino, C _1-4 alkylamino or C _2-8 dialkyl Amino, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl may be 1, 2 or 3 halo, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _{1- 4} haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO ₂ , OR ^a , SR ^a , C (O) R ^b , C (O) NR ^c R ^d , C (O) OR ^a , OC (O) R ^b , OC (O) NR ^c R ^d , NR ^c R ^d , NR ^c C (O) R ^d , NR ^c C (O) OR ^a , S (O) R ^b , S (O) Optionally substituted by NR ^c R ^d , S (O) ₂ R ^b , or S (O) ₂ NR ^c R ^d , Wherein two W-X-Y-Z bonded to the same atom optionally form a 3- to 14-membered cycloalkyl or heterocycloalkyl group optionally substituted by 1, 2 or 3 W "-X" -Y "-Z"; Wherein two W'-X'-Y'-Z 'bonded to the same atom are 3- to 14-membered cycloalkyl optionally substituted by 1, 2 or 3 W "-X" -Y "-Z" Or optionally forms a heterocycloalkyl group; Wherein W-X-Y-Z is not H; Wherein W'-X'-Y'-Z 'is not H; Wherein W "-X" -Y "-Z" is not H; R ^a and R ^{a '} are each independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocyclo Alkyl, wherein C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl; Heterocycloalkyl, heterocycloalkylalkyl is selected from H, OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl Optionally substituted; R ^b and R ^{b ′} are each independently H, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclo Alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, Cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is H, OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1- Optionally substituted by ₆ haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; R ^c and R ^d are each independently H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, Arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl , Cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is H, OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 halo Optionally substituted by alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or R ^c and R ^d together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group; R ^{c '} and R ^d' are each independently H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclo Alkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, Heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is H, OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1- Optionally substituted by ₆ haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or R ^{c '} and R ^d' together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group; R ^e and R ^f are each independently H, C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl , Arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C _1-10 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, aryl, hetero Aryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is H, OH, amino, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 Optionally substituted by haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl or heterocycloalkyl; or R ^e and R ^f together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group; q is 1 or 2. The compound of claim 15, wherein Ar is aryl optionally substituted by 1, 2, 3, 4 or 5 W—X—Y—Z. 16. The compound of claim 15, wherein Ar is phenyl or naphthyl, optionally substituted by 1, 2, 3, 4 or 5 W-X-Y-Z, respectively. The compound of claim 15, wherein Ar is 1, 2 or 3 halo; Nitro; Cyano; C _{1 -4} alkyl; C _{1 -4} haloalkyl; C _{1 -4} alkoxy; C _{1 -4} haloalkoxy; Dialkylamino; Dialkylaminocarbonyl; Alkylsulfonyl; Cycloalkyloxy; Heteroaryloxy; Aryloxy; Cycloalkyl; Heterocycloalkyl; Phenyl optionally substituted by one or more halo, cyano, C _1-4 alkyl, C _1-4 alkoxy or —NHC (O) — (C _1-4 alkyl); A (C _{1 -4} alkyl) in an optionally substituted pyridyl, optionally substituted by phenyl or by naphthyl, - or one or more halo, cyano, C _1-4 alkyl, C _1-4 alkoxy, or -NHC (O) compound. 16. The compound of claim 15, wherein Ar is heteroaryl optionally substituted by 1, 2, 3, 4 or 5 W-X-Y-Z. 16. The compound of claim 15, wherein Ar is pyridyl, pyrimidinyl, thienyl, thiazolyl, quinolinyl, 2,1,3-benzone, each optionally substituted with 1, 2, 3, 4, or 5 WXYZ, respectively. Diazolyl, isoquinolinyl or isoxazolyl. 16. The compound of claim 15, wherein Ar is pyridyl, thienyl, or isoxazolyl, each optionally substituted with 1, 2, 3, 4 or 5 W-X-Y-Z. 16. The compound of claim 15, wherein Ar is pyridyl, quinolinyl, 2,1,3-benzoxadiazolyl, isoqui, optionally substituted with 1, 2 or 3 halo, C _1-4 alkyl or aryloxy, respectively. Nolinyl, thienyl or isoxazolyl. The compound of claim 15, wherein q is 1. 16. The compound of claim 15, wherein R ³ is aryl, cycloalkyl or heteroaryl optionally substituted by 1, 2 or 3 W'-X'-Y'-Z '. The compound of claim 15, wherein R ³ is 1, 2 or 3 halo, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, phenyl, halo-substituted phenyl, phenyloxy, pyridyl , acyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, or one or two halo or C _1-4 a by the arylsulfonyl optionally substituted by alkyl, optionally substituted C _1-4 alkyl, aryl, cycloalkyl , Heteroaryl or heterocycloalkyl. 16. The compound of claim 15, wherein R ³ is each aryl or cycloalkyl, optionally substituted by 1, 2 or 3 W'-X'-Y'-Z '. 16. The compound of claim 15, wherein R ³ is cycloheptyl, cyclohexyl, cyclopentyl, cyclopropyl, 1,2,3, each optionally substituted by 1, 2 or 3 W'-X'-Y'-Z '. 4-tetrahydronaphthalenyl, norbornyl or adamantyl. 16. The compound of claim 15, wherein R ³ is phenyl or naphthyl, optionally substituted by 1, 2 or 3 W'-X'-Y'-Z ', respectively. The compound of claim 15, wherein R ³ is 1, 2 or 3 halo, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _2-8 alkoxyalkyl , Aryl, aryloxy, pyridyl or phenyl or naphthyl optionally substituted by azepan-2-one-yl. The phenyl or naphthyl of claim 15, wherein R ³ is each optionally substituted with 1, 2 or 3 halo, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, aryl or aryloxy. Phosphorus compounds. 16. The compound of claim 15, wherein R ³ is heteroaryl or heterocycloalkyl, each optionally substituted by 1, 2 or 3 W'-X'-Y'-Z '. 16. The compound of claim 15, wherein R ³ is piperidinyl optionally substituted by 1, 2 or 3 W'-X'-Y'-Z '. The compound of claim 15, wherein R ³ is 1, 2 or 3 CO— (C _1-4 alkyl), C (O) O— (C _1-4 alkyl), SO ₂ — (C _1-4 alkyl), SO ₂ - or aryl SO ₂ - (1 or 2 halo or aryl optionally substituted by C _1-4 alkyl), the piperidinyl compound is optionally substituted. 16. The compound of claim 15, wherein R ³ is pyridyl optionally substituted by 1, 2 or 3 W'-X'-Y'-Z '. The compound of claim 15, wherein R ³ is pyridyl. The compound of claim 15, wherein R ³ is 8-aza-bicyclo [3.2.1] octanyl, indolyl, morpholino, S-oxo-thiomorpholino, S, S-dioxo-thiomorpholino Or thiomorpholino. The compound of claim 15, wherein R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each H. 16. The compound of claim 15, wherein R ¹ is H. 16. The compound of claim 15, wherein R ² is H. 16. 16. A compound of formula II according to claim 15. Formula II

41. The compound of claim 40, wherein Ar is one or two halo, cyano, nitro, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, aryloxy, hetero Phenyl, naphthyl, pyridyl, thienyl, isoxazolyl, quinolinyl, isoquinolinyl or 2,1,3-benzoxa, optionally substituted by aryloxy, acylamino, alkylsulfonyl or dialkylamino Diazolyl. 41. The compound of claim 40, wherein R ³ is each substituted by one or two OH, C _1-4 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, phenyl, naphthyl, pyri Dill, piperidinyl, morpholino, S-oxo-thiomorpholino, S, S-dioxo-thiomorpholino, thiomorpholino or 8-aza-bicyclo [3.2.1] octanyl; C _1-4 alkyl; C _1-4 alkoxy; C _1-4 haloalkyl; Phenyl; Phenyloxy; Arylsulfonyl optionally substituted by 1 or 2 halo or C _1-4 alkyl; Chlorophenyl; Alkylcarbonyl; Alkoxycarbonyl; Or alkylsulfonyl. The method of claim 15, Ar is aryl or heteroaryl, optionally substituted by 1, 2, 3, 4 or 5 W-X-Y-Z, respectively; R ¹ is H, C (O) OR ^{b '} , S (O) R ^a' , S (O) NR ^{c '} R ^d' , S (O) ₂ R ^{a '} , S (O) ₂ NR ^c' R ^{d '} , C _1-10 alkyl, C _1-10 haloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cyclo Alkylalkyl or heterocycloalkylalkyl, wherein C _1-10 alkyl, C _1-10 haloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, Arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted by 1, 2 or 3 R ¹⁴ ; R ² is H or C _1-6 alkyl; R ³ is each H, C _1-6 alkyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl optionally substituted by 1, 2 or 3 W'-X'-Y'-Z '; R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each independently H, OC (O) R ^{a '} , OC (O) OR ^b' , C (O) OR ^{b '} , OC (O) NR ^c' R ^{d '} , NR ^c' R ^{d '} , NR ^c' C (O) R ^{a '} , NR ^c' C (O) OR ^{b '} , S (O) R ^a' , S (O) NR ^{c '} R ^d' , S (O) ₂ R ^{a '} , S (O) ₂ NR ^c' R ^{d '} , SR ^b' , C _1-10 alkyl, C _1-10 haloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein C _1-10 alkyl , C _1-10 haloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl A compound optionally substituted by 1, 2 or 3 R ¹⁴ . The method of claim 15, Ar is aryl or heteroaryl, optionally substituted by 1, 2, 3, 4 or 5 W-X-Y-Z, respectively; R ¹ is H; R ² is H; R ³ is each C _1-6 alkyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl optionally substituted by 1, 2 or 3 W'-X'-Y'-Z '; R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each H. The compound of claim 15, wherein R ³ is substituted piperidinyl. N- (3R) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-ylcyclohexanecarboxamide; N- (3R) -1-[(2-nitrophenyl) sulfonyl] piperidin-3-ylcyclohexanecarboxamide; N-[(3R) -1- (2-naphthylsulfonyl) piperidin-3-yl] cyclohexanecarboxamide; N- (3R) -1-[(3-chlorophenyl) sulfonyl] piperidin-3-ylcyclohexanecarboxamide; N- (3R) -1-[(4-propylphenyl) sulfonyl] piperidin-3-ylcyclohexanecarboxamide; N-{(3R) -1-[(4-fluorophenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide; N-{(3R) -1-[(3-methoxyphenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide; N- (3R) -1-[(3-chloro-4-fluorophenyl) sulfonyl] piperidin-3-ylcyclohexanecarboxamide; 1- (4-chlorophenyl) -N-[(3R) -1- (phenylsulfonyl) piperidin-3-yl] cyclohexanecarboxamide; 1-methyl-N-[(3R) -1- (phenylsulfonyl) piperidin-3-yl] cyclohexanecarboxamide; 4-hydroxy-N-[(3R) -1- (phenylsulfonyl) piperidin-3-yl] cyclohexanecarboxamide; 4-methoxy-N-[(3R) -1- (phenylsulfonyl) piperidin-3-yl] cyclohexanecarboxamide; N-[(3S) -1- (phenylsulfonyl) piperidin-3-yl] cyclohexanecarboxamide; N-{(3S) -1-[(2-fluorophenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide; N-{(3S) -1-[(2-chlorophenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide; N-{(3S) -1-[(2-bromophenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide; N-{(3S) -1-[(2-cyanophenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide; N-{(3S) -1-[(2-nitrophenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide; N-{(3S) -1-[(2-methylphenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide; N-((3S) -1-{[2- (trifluoromethyl) phenyl] sulfonyl} piperidin-3-yl) cyclohexanecarboxamide; N-((3S) -1-{[2- (trifluoromethoxy) phenyl] sulfonyl} piperidin-3-yl) cyclohexanecarboxamide; N-{(3S) -1-[(2-phenoxyphenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide; N-{(3S) -1-[(3-chlorophenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide; N-{(3S) -1-[(3-cyanophenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide; N-{(3S) -1-[(3-methylphenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide; N-((3S) -1-{[3- (trifluoromethyl) phenyl] sulfonyl} piperidin-3-yl) cyclohexanecarboxamide; N-{(3S) -1-[(3-phenoxyphenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide; N-{(3S) -1-[(4-fluorophenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide; N-{(3S) -1-[(4-chlorophenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide; N-{(3S) -1-[(4-methoxyphenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide; N-((3S) -1-{[4- (trifluoromethoxy) phenyl] sulfonyl} piperidin-3-yl) -cyclohexanecarboxamide; N- (3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-ylcyclohexanecarboxamide; N-((3S) -1-{[4- (acetylamino) phenyl] sulfonyl} piperidin-3-yl) cyclohexanecarboxamide; N-{(3S) -1-[(4-isopropylphenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide; N-{(3S) -1-[(4-methylphenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide; N-((3S) -1-{[4- (methylsulfonyl) phenyl] sulfonyl} piperidin-3-yl) cyclohexanecarboxamide; N-((3S) -1-{[4- (pyridin-4-yloxy) phenyl] sulfonyl} piperidin-3-yl) cyclohexanecarboxamide; N-((3S) -1-{[4- (pyridin-3-yloxy) phenyl] sulfonyl} piperidin-3-yl) cyclohexanecarboxamide; N-{(3S) -1-[(4-tert-butylphenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide; N-{(3S) -1-[(4-fluoro-2-methylphenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide; N-{(3S) -1-[(2,3-dichlorophenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide; N-{(3S) -1-[(2,6-dichlorophenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide; N-{(3S) -1-[(2,5-dichlorophenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide; N-{(3S) -1-[(3,4-dichlorophenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide; N-{(3S) -1-[(3-chloro-4-fluorophenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide; N-{(3S) -1-[(5-chloro-2-fluorophenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide; N-{(3S) -1-[(3-chloro-2-fluorophenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide; N-{(3S) -1-[(2,6-difluorophenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide; N-{(3S) -1-[(3,4-dimethoxyphenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide; N-{(3S) -1-[(2,5-dimethoxyphenyl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide; N-[(3S) -1- (1-naphthylsulfonyl) piperidin-3-yl] cyclohexanecarboxamide; N-[(3S) -1- (pyridin-3-ylsulfonyl) piperidin-3-yl] cyclohexanecarboxamide; N-[(3S) -1- (2-thienylsulfonyl) piperidin-3-yl] cyclohexanecarboxamide; N-{(3S) -1-[(3,5-dimethylisoxazol-4-yl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide; N-{(3S) -1-[(4-phenoxypyridin-3-yl) sulfonyl] piperidin-3-yl} cyclohexanecarboxamide; N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} cyclopentanecarboxamide; N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} adamantane-1-carbox amide; N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -2-methylpropanamide; N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -2,2-dimethylpropanamide; N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -2,2-diphenylacetamide; 1-acetyl-N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} piperidine-4-carboxamide; N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -1- (4-chlorophenyl) cyclopentanecarboxamide; N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -1-methylcyclohexanecarboxamide; N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -3-methoxycyclohexanecarboxamide;  Trans-N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -3-methoxycyclohexanecarboxamide; N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -4-methoxycyclohexanecarboxamide;  Trans-N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -4-methoxy cyclohexanecarboxamide; N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -4-hydroxycyclohexanecarboxamide;  Trans-N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -4-hydroxycyclohexanecarboxamide; N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -1-phenylcyclopropanecarboxamide; N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} biphenyl-2-carboxamide; N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} cycloheptancarboxamide;  Tert-butyl (3S) -3-[((3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-ylamino) carbonyl] piperidine-1-carboxyl Rate; (3S) -N- (3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl-1- (methylsulfonyl) piperidine-3-carboxamide; (3S) -N- (3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl-1- (methylsulfonyl) piperidine-3-carboxamide; (3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] -N- (3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-ylpiperidine -3-carboxamide; N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} benzamide; N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -2-methylbenzamide; N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -2-chlorobenzamide; N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -3-fluorobenzamide; N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -3-methoxybenzamide; N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -3- (trifluoromethyl) benzamide; N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} pyridine-2-carboxamide; N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} pyridine-3-carboxamide; N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} pyridine-4-carboxamide; N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -4-methoxybenzamide; N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -3-phenoxybenzamide; N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -1-naphthamide; N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -2-methoxybenzamide; N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -2,5-difluorobenzamide; N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -2-fluoro-4- (trifluoromethyl) benzamide; N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -4-fluoro-3- (trifluoromethyl) benzamide; N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -2-fluoro-5- (trifluoromethyl) benzamide; N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -3,5-difluorobenzamide; N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -2,6-difluorobenzamide; 4-hydroxy -N - [(3 S) -1- phenyl-piperidin-3-yl] cyclohexane-carboxamide; 4-methoxy-N-[(3S) -1-phenylpiperidin-3-yl] cyclohexanecarboxamide; 4- (hydroxymethyl) -N-[(3S) -1-phenylpiperidin-3-yl] cyclohexanecarboxamide; 2-hydroxy-N-[(3S) -1-phenylpiperidin-3-yl] bicyclo [3.2.1] octane-6-carboxamide; N-[(3S) -1-phenylpiperidin-3-yl] adamantane-1-carboxamide; 3-hydroxy-N-[(3S) -1-phenylpiperidin-3-yl] adamantane-1-carboxamide; N-[(3S) -1-phenylpiperidin-3-yl] cyclohexanecarboxamide; 1-methyl-N-[(3S) -1-phenylpiperidin-3-yl] cyclohexanecarboxamide; 4-methyl-N-[(3S) -1-phenylpiperidin-3-yl] cyclohexanecarboxamide; 4-ethyl-N-[(3S) -1-phenylpiperidin-3-yl] cyclohexanecarboxamide; 3-methoxy-N-[(3S) -1-phenylpiperidin-3-yl] cyclohexanecarboxamide; 4-methoxy-N-[(3S) -1-phenylpiperidin-3-yl] cyclohexanecarboxamide; N-[(3S) -1-phenylpiperidin-3-yl] bicyclo [2.2.1] heptane-2-carboxamide; N-[(3S) -1-phenylpiperidin-3-yl] cycloheptancarboxamide; N-[(3S) -1-phenylpiperidin-3-yl] -1,2,3,4-tetrahydronaphthalene-2-carboxamide; 2-methyl-N-[(3S) -1-phenylpiperidin-3-yl] benzamide; 5-chloro-2-methyl-N-[(3S) -1-phenylpiperidin-3-yl] benzamide; N-[(3S) -1-phenylpiperidin-3-yl] biphenyl-4-carboxamide; 3-methoxy-N-[(3S) -1-phenylpiperidin-3-yl] benzamide; 4-methoxy-N-[(3S) -1-phenylpiperidin-3-yl] benzamide; 4-phenoxy-N-[(3S) -1-phenylpiperidin-3-yl] benzamide; 2- (2-methyl-1H-indol-3-yl) -N-[(3S) -1-phenylpiperidin-3-yl] acetamide; N-[(3S) -1-phenylpiperidin-3-yl] -1H-indole-3-carboxamide; N-[(3S) -1-phenylpiperidin-3-yl] -1H-indole-2-carboxamide; 1-methyl-N-[(3S) -1-phenylpiperidin-3-yl] -1H-indole-2-carboxamide; 2-methyl-N-[(3S) -1-phenylpiperidin-3-yl] quinoline-3-carboxamide; N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} piperidine-1-carboxamide; N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -4-hydroxypiperidine-1-carboxamide; N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} morpholine-4-carboxamide; N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} thiomorpholine-4-carboxamide; N-{(3S) -1-[(3-chloro-2-fluorophenyl) sulfonyl] piperidin-3-yl} piperidine-1-carboxamide; N-{(3S) -1-[(3-chloro-2-fluorophenyl) sulfonyl] piperidin-3-yl} -4-hydroxypiperidine-1-carboxamide; N-{(3S) -1-[(3-chloro-2-fluorophenyl) sulfonyl] piperidin-3-yl} morpholine-4-carboxamide; N-{(3S) -1-[(3-chloro-2-fluorophenyl) sulfonyl] piperidin-3-yl} thiomorpholine-4-carboxamide; N-{(3S) -1-[(2,6-dichlorophenyl) sulfonyl] piperidin-3-yl} piperidine-1-carboxamide; N-{(3S) -1-[(2,6-dichlorophenyl) sulfonyl] piperidin-3-yl} -4-hydroxypiperidine-1-carboxamide; N-{(3S) -1-[(2,6-dichlorophenyl) sulfonyl] piperidin-3-yl} morpholine-4-carboxamide; N-{(3S) -1-[(2,6-dichlorophenyl) sulfonyl] piperidin-3-yl} thiomorpholine-4-carboxamide; N-{(3S) -1-[(3-chloro-2-fluorophenyl) sulfonyl] piperidin-3-yl} thiomorpholine-4-carboxamide 1-oxide; N-{(3S) -1-[(3-chloro-2-fluorophenyl) sulfonyl] piperidin-3-yl} thiomorpholine-4-carboxamide 1,1-dioxide; N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} thiomorpholine-4-carboxamide 1,1-dioxide; N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} thiomorpholine-4-carboxamide 1-oxide; N-{(3S) -1-[(2,6-dichlorophenyl) sulfonyl] piperidin-3-yl} thiomorpholine-4-carboxamide 1-oxide; N-{(3S) -1-[(2,6-dichlorophenyl) sulfonyl] piperidin-3-yl} thiomorpholine-4-carboxamide 1,1-dioxide; 4-hydroxy-N-[(3S) -1-phenylpiperidin-3-yl] adamantane-1-carboxamide; N-[(3S) -1-phenylpiperidin-3-yl] -1-pyridin-4-ylcyclobutanecarboxamide; N-[(3S) -1-phenylpiperidin-3-yl] -1-pyridin-3-ylcyclobutanecarboxamide; 1-phenyl-N-[(3S) -1-phenylpiperidin-3-yl] cyclopropanecarboxamide; Methyl 4- {3-fluoro-4- [1-({[(3S) -1-phenylpiperidin-3-yl] amino} -carbonyl) -cyclopropyl] phenyl} piperazin-1-carboxyl Rate;  Benzyl (3S) -3-{[(4-hydroxy-1-adamantyl) carbonyl] amino} piperidine-1-carboxylate; 4-hydroxy-N-{(3S) -1- [6- (trifluoromethyl) pyridin-2-yl] piperidin-3-yl} adamantane-1-carboxamide; 4-hydroxy-N-{(3S) -1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-3-yl} adamantane-1-carboxamide; 4-hydroxy-N-[(3S) -1- (5-nitropyridin-2-yl) piperidin-3-yl] adamantane-1-carboxamide; N-[(3S) -1- (5-cyanopyridin-2-yl) piperidin-3-yl] -4-hydroxyadamantane-1-carboxamide; 6-((3S) -3-{[(4-hydroxy-1-adamantyl) carbonyl] amino} piperidin-1-yl) -N, N-dimethylnicotinamide; Methyl 6-((3S) -3-{[(4-hydroxy-1-adamantyl) carbonyl] amino} piperidin-1-yl) nicotinate; 4-hydroxy-N-{(3S) -1- [4- (trifluoromethyl) phenyl] piperidin-3-yl} adamantane-1-carboxamide; 4-hydroxy-N-{(3S) -1- [4- (trifluoromethoxy) phenyl] piperidin-3-yl} adamantane-1-carboxamide; N-{(3S) -1- [4- (benzyloxy) phenyl] piperidin-3-yl} -4-hydroxyadamantane-1-carboxamide; N-[(3S) -1- (3-fluoropyridin-4-yl) piperidin-3-yl] -4-hydroxyadamantane-1-carboxamide; 4-hydroxy-N-[(3S) -1- (1,3-thiazol-2-yl) piperidin-3-yl] adamantane-1-carboxamide; (3S) -3-{[(4-hydroxy-1-adamantyl) carbonyl] amino} -N-phenylpiperidine-1-carboxamide; N-[(3S) -1-benzoylpiperidin-3-yl] -4-hydroxyadamantane-1-carboxamide; 4-hydroxy-N-[(3S) -1- (4-pyridin-3-ylphenyl) piperidin-3-yl] adamantane-1-carboxamide; N-{(3S) -1- [5- (4-chlorophenyl) pyridin-2-yl] piperidin-3-yl} -4-hydroxyadamantane-1-carboxamide; 4-hydroxy-N-[(3S) -1- (4-pyridin-2-ylphenyl) piperidin-3-yl] adamantane-1-carboxamide; (1S, 5S) -3-hydroxy-N-[(3S) -1- (1-naphthylsulfonyl) piperidin-3-yl] -8-azabicyclo [3.2.1] octane-8- Carboxamide; (1S, 5S) -N-{(3S) -1-[(2,6-dichlorophenyl) sulfonyl] piperidin-3-yl} -3-hydroxy-8-azabicyclo [3.2.1 ] Octane-8-carboxamide; (1S, 5S) -N-{(3S) -1-[(3-chloro-2-fluorophenyl) sulfonyl] piperidin-3-yl} -3-hydroxy-8-azabicyclo [ 3.2.1] octane-8-carboxamide; (1S, 5S) -N-{(3S) -1-[(3-chloro-2-methylphenyl) sulfonyl] piperidin-3-yl} -3-hydroxy-8-azabicyclo [3.2. 1] octane-8-carboxamide;  (1S, 5S) -N-{(3S) -1-[(3-chlorophenyl) sulfonyl] piperidin-3-yl} -3-hydroxy-8-azabicyclo [3.2.1] octane -8-carboxamide; (1S, 5S) -3-hydroxy-N-{(3S) -1-[(3-methylphenyl) sulfonyl] piperidin-3-yl} -8-azabicyclo [3.2.1] octane- 8-carboxamide; (1S, 5S) -N-{(3S) -1-[(2-fluorophenyl) sulfonyl] piperidin-3-yl} -3-hydroxy-8-azabicyclo [3.2.1] Octane-8-carboxamide; (1S, 5S) -3-hydroxy-N-{(3S) -1-[(2-methylphenyl) sulfonyl] piperidin-3-yl} -8-azabicyclo [3.2.1] octane- 8-carboxamide; N-((3S) -1- {4- [2- (diethylamino) -2-oxoethoxy] phenyl} piperidin-3-yl) -4-hydroxyadamantane-1-carbox amides; N-((3S) -1- {4-[(cyclopropylcarbonyl) (methyl) amino] phenyl} piperidin-3-yl) -4-hydroxyadamantane-1-carboxamide; 7-oxo-N-{(3S) -1- [4- (trifluoromethoxy) phenyl] piperidin-3-yl} azane-4-carboxamide; 7-oxo-N-{(3S) -1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-3-yl} azane-4-carboxamide; 7-oxo-N-[(3S) -1-phenylpiperidin-3-yl] azane-4-carboxamide; N-[(3S) -1- (2-fluoro-4-pyridin-4-ylphenyl) piperidin-3-yl] -4-hydroxyadamantane-1-carboxamide; 4-hydroxy-N-[(3S) -1- (1-naphthylsulfonyl) piperidin-3-yl] piperidine-1-carboxamide; N-{(3S) -1- [4- (difluoromethoxy) phenyl] piperidin-3-yl} -4-hydroxyadamantane-1-carboxamide; N-{(3S) -1- [3-fluoro-5- (trifluoromethyl) phenyl] piperidin-3-yl} -4-hydroxyadamantane-1-carboxamide; N-{(3S) -1- [3- (difluoromethoxy) phenyl] piperidin-3-yl} -4-hydroxyadamantane-1-carboxamide; 4-hydroxy-N-{(3S) -1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-3-yl} adamantane-1-carboxamide; N-{(3S) -1- [3-chloro-5- (trifluoromethyl) pyridin-2-yl] piperidin-3-yl} -4-hydroxyadamantane-1-carboxamide ; 4-hydroxy-N-{(3S) -1- [6-methyl-4- (trifluoromethyl) pyridin-2-yl] piperidin-3-yl} adamantane-1-carboxamide ; 4-hydroxy-N-[(3S) -1- (6-methylpyridin-2-yl) piperidin-3-yl] adamantane-1-carboxamide; N-[(3S) -1- (6-fluoropyridin-2-yl) piperidin-3-yl] -4-hydroxyadamantane-1-carboxamide; 4-hydroxy-N-[(3S) -1- (4-methylpyridin-2-yl) piperidin-3-yl] adamantane-1-carboxamide; 4-hydroxy-N-[(3S) -1- (4-methoxypyridin-2-yl) piperidin-3-yl] adamantane-1-carboxamide; 4-hydroxy-N-[(3S) -1- (6-methoxypyridin-2-yl) piperidin-3-yl] adamantane-1-carboxamide; N-[(3S) -1- (5-fluoropyridin-2-yl) piperidin-3-yl] -4-hydroxyadamantane-1-carboxamide; 4-hydroxy-N-[(3S) -1- (5-methylpyridin-2-yl) piperidin-3-yl] adamantane-1-carboxamide; N-[(3S) -1- (5-chloropyridin-2-yl) piperidin-3-yl] -4-hydroxyadamantane-1-carboxamide; N-[(3S) -1- (2,5-difluoropyridin-3-yl) piperidin-3-yl] -4-hydroxyadamantane-1-carboxamide; N-[(3S) -1- (3,5-difluoropyridin-2-yl) piperidin-3-yl] -4-hydroxyadamantane-1-carboxamide; N-{(3S) -1- [4- (cyclohexyloxy) phenyl] piperidin-3-yl} -4-hydroxyadamantane-1-carboxamide; N-{(3S) -1- [4- (cyclopentyloxy) phenyl] piperidin-3-yl} -4-hydroxyadamantane-1-carboxamide; 4-hydroxy-N-[(3S) -1-phenylpiperidin-3-yl] piperidine-1-carboxamide; (1S, 5S) -3-hydroxy-N-[(3S) -1-phenylpiperidin-3-yl] -8-azabicyclo [3.2.1] octane-8-carboxamide; N-[(3S) -1- (3,4'-bipyridin-6-yl) piperidin-3-yl] -4-hydroxyadamantane-1-carboxamide; N-((3S) -1- {5- [4- (acetylamino) phenyl] pyridin-2-yl} piperidin-3-yl) -4-hydroxyadamantane-1-carboxamide; N-{(3S) -1- [5- (4-cyanophenyl) pyridin-2-yl] piperidin-3-yl} -4-hydroxyadamantane-1-carboxamide; 4-hydroxy-N-{(3S) -1- [4- (2-oxopyrrolidin-1-yl) phenyl] piperidin-3-yl} adamantane-1-carboxamide; 4-hydroxy-N-{(3S) -1- [5- (4-methoxyphenyl) pyridin-2-yl] piperidin-3-yl} adamantane-1-carboxamide; Ethyl [4-((3S) -3-{[(4-hydroxy-1-adamantyl) carbonyl] amino} piperidin-1-yl) phenyl] methylcarbamate; N-[(3S) -1- (5- {4-[(cyclopropylamino) carbonyl] phenyl} pyridin-2-yl) piperidin-3-yl] -4-hydroxyadamantane-1 Carboxamide; N-[(3S) -1- (6'-fluoro-3,3'-bipyridin-6-yl) piperidin-3-yl] -4-hydroxyadamantane-1-carboxamide ; Tert-butyl4- [4-((3S) -3-{[(4-hydroxy-1-adamantyl) carbonyl] amino} piperidin-1-yl) phenoxy] piperidine- 1-carboxylate; 4-hydroxy-N-[(3S) -1- (6'-methoxy-3,3'-bipyridin-6-yl) piperidin-3-yl] adamantane-1-carboxamide ; 6 '-((3S) -3-{[(4-hydroxy-1-adamantyl) carbonyl] amino} piperidin-1-yl) -3,3'-bipyridine-6-carbox amides; 4-hydroxy-N-[(3S) -1- (quinolin-8-ylsulfonyl) piperidin-3-yl] piperidine-1-carboxamide; N-((3S) -1-{[5- (dimethylamino) -1-naphthyl] sulfonyl} piperidin-3-yl) -4-hydroxypiperidine-1-carboxamide; (3-exo) -N-((3S) -1-{[5- (dimethylamino) -1-naphthyl] sulfonyl} piperidin-3-yl) -3-hydroxy-8-azabi Cyclo [3.2.1] octane-8-carboxamide; (3-endo) -N-((3S) -1-{[5- (dimethylamino) -1-naphthyl] sulfonyl} piperidin-3-yl) -3-hydroxy-8-azabi Cyclo [3.2.1] octane-8-carboxamide; 3-hydroxy-N-[(3S) -1- (quinolin-8-ylsulfonyl) piperidin-3-yl] -8-azabicyclo [3.2.1] octane-8-carboxamide; N-[(3S) -1- (2-fluorophenyl) piperidin-3-yl] -3-hydroxy-8-azabicyclo [3.2.1] octane-8-carboxamide; N-[(3S) -1- (4-fluorophenyl) piperidin-3-yl] -3-hydroxy-8-azabicyclo [3.2.1] octane-8-carboxamide; (3-endo) -N-[(3S) -1- (4-cyanophenyl) piperidin-3-yl] -3-hydroxy-8-azabicyclo [3.2.1] octane-8- Carboxamides; (3-endo) -3-hydroxy-N-{(3S) -1- [4- (methylsulfonyl) phenyl] piperidin-3-yl} -8-azabicyclo [3.2.1] octane -8-carboxamide; (3-endo) -3-hydroxy-N-{(3S) -1- [4- (trifluoromethoxy) phenyl] piperidin-3-yl} -8-azabicyclo [3.2.1] Octane-8-carboxamide; N-{(3S) -1-[(4-chloro-1-naphthyl) sulfonyl] piperidin-3-yl} -4-hydroxypiperidine-1-carboxamide; N-[(3S) -1- (5-ethylpyrimidin-2-yl) piperidin-3-yl] -4-hydroxyadamantane-1-carboxamide; 4-hydroxy-N-{(3S) -1- [4- (trifluoromethyl) pyrimidin-2-yl] piperidin-3-yl} adamantane-1-carboxamide; N-[(3S) -1- (2-chloropyrimidin-4-yl) piperidin-3-yl] -4-hydroxyadamantane-1-carboxamide; N-[(3S) -1- (4-chloropyrimidin-2-yl) piperidin-3-yl] -4-hydroxyadamantane-1-carboxamide; 4-hydroxy-N-[(3S) -1- (4-pyridin-4-ylphenyl) piperidin-3-yl] adamantane-1-carboxamide; N-{(3S) -1- [4- (3-fluoropyridin-4-yl) phenyl] piperidin-3-yl} -4-hydroxyadamantane-1-carboxamide; 4-hydroxy-N-[(3S) -1- (isoquinolin-5-ylsulfonyl) piperidin-3-yl] piperidine-1-carboxamide; (3-endo) -3-hydroxy-N-[(3S) -1- (isoquinolin-5-ylsulfonyl) piperidin-3-yl] -8-azabicyclo [3.2.1] octane- 8-carboxamide; (3-endo) -3-hydroxy-N-[(3S) -1- (2-naphthylsulfonyl) piperidin-3-yl] -8-azabicyclo [3.2.1] octane-8- Carboxamide; (3-exo) -3-hydroxy-N-[(3S) -1- (2-naphthylsulfonyl) piperidin-3-yl] -8-azabicyclo [3.2.1] octane-8- Carboxamide; (3-exo) -N-{(3S) -1-[(4-chloro-1-naphthyl) sulfonyl] piperidin-3-yl} -3-hydroxy-8-azabicyclo [3.2 .1] octane-8-carboxamide; (3-endo) -N-{(3S) -1-[(4-chloro-1-naphthyl) sulfonyl] piperidin-3-yl} -3-hydroxy-8-azabicyclo [3.2 .1] octane-8-carboxamide; 4-hydroxy-N-[(3S) -1- (2-naphthylsulfonyl) piperidin-3-yl] piperidine-1-carboxamide; N-[(3S) -1- (2,1,3-benzoxadiazol-4-ylsulfonyl) piperidin-3-yl] -4-hydroxypiperidine-1-carboxamide; (3-endo) -N-[(3S) -1- (2,1,3-benzoxadiazol-4-ylsulfonyl) piperidin-3-yl] -3-hydroxy-8-azabi Cyclo [3.2.1] octane-8-carboxamide; 6-((3S) -3-{[(4-hydroxy-1-adamantyl) carbonyl] amino} piperidin-1-yl) -N, N-dimethylnicotinamide; Tert-butyl 6-[(3S) -3-({[4- (acetyloxy) -1-adamantyl] carbonyl} amino) piperidin-1-yl] -3 ', 6'-di Hydro-3,4'-bipyridine-1 '(2'H) -carboxylate; Benzyl (3S) -3-{[(5-oxo-4-azatricyclo [4.3.1.1 (3,8)] undec-1-yl) carbonyl] amino} piperidine-1-carboxylate; (3-endo) -3-hydroxy-N-[(3S) -1- (4-nitrophenyl) piperidin-3-yl] -8-azabicyclo [3.2.1] octane-8-car Boxamide; N-((3S) -1- {4-[(1-acetylpiperidin-4-yl) oxy] phenyl} piperidin-3-yl) -4-hydroxyadamantane-1-carbox amides; Methyl 4- [4-((3S) -3-{[(4-hydroxy-1-adamantyl) carbonyl] amino} piperidin-1-yl) phenoxy] piperidine-1-carboxyl Rate; 4-hydroxy-N-[(3S) -1- (4-{[1- (methylsulfonyl) piperidin-4-yl] oxy} phenyl) piperidin-3-yl] adamantane- 1-carboxamide; N-((3S) -1- {4- [acetyl (methyl) amino] phenyl} piperidin-3-yl) -4-hydroxyadamantane-1-carboxamide; (3-endo) -N-[(3S) -1- (4-aminophenyl) piperidin-3-yl] -3-hydroxy-8-azabicyclo [3.2.1] octane-8-car Boxamide; (3-endo) -3-hydroxy-N-((3S) -1- {4-[(methylsulfonyl) amino] phenyl} piperidin-3-yl) -8-azabicyclo [3.2. 1] octane-8-carboxamide; Ethyl {4-[(3S) -3-({[(3-endo) -3-hydroxy-8-azabicyclo [3.2.1] oct-8-yl] carbonyl} amino) piperidine- 1-yl] phenyl} carbamate; (3-endo) -3-hydroxy-N-{(3S) -1- [4- (2-oxopiperidin-1-yl) phenyl] piperidin-3-yl} -8-azabi Cyclo [3.2.1] octane-8-carboxamide; N-{(3S) -1- [4- (acetylamino) phenyl] piperidin-3-yl} -4-hydroxyadamantane-1-carboxamide; N-{(3S) -1- [4- (acetylamino) phenyl] piperidin-3-yl} -4-oxoadamantane-1-carboxamide; N-((3S) -1- {4-[(cyclopropylcarbonyl) amino] phenyl} piperidin-3-yl) -4-hydroxyadamantane-1-carboxamide; 4-hydroxy-4-methyl-N-{(3S) -1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-3-yl} adamantane-1-carboxamide ; Methyl [4-((3S) -3-{[(4-hydroxy-1-adamantyl) carbonyl] amino} piperidin-1-yl) phenyl] carbamate; (3-endo) -3-hydroxy-N-{(3S) -1- [4- (trifluoromethyl) phenyl] piperidin-3-yl} -8-azabicyclo [3.2.1] Octane-8-carboxamide; (3-endo) -N-[(3S) -1-biphenyl-4-ylpiperidin-3-yl] -3-hydroxy-8-azabicyclo [3.2.1] octane-8-carbox amides; (3-endo) -N-((3S) -1- {4-[(cyclopropylacetyl) amino] phenyl} piperidin-3-yl) -3-hydroxy-8-azabicyclo [3.2. 1] octane-8-carboxamide; (3-endo) -3-hydroxy-N-{(3S) -1- [4- (2-oxopyrrolidin-1-yl) phenyl] piperidin-3-yl} -8-azabi Cyclo [3.2.1] octane-8-carboxamide; (3-endo) -3-hydroxy-N-{(3S) -1- [5- (trifluoromethyl) pyridin-2-yl] piperidin-3-yl} -8-azabicyclo [ 3.2.1] octane-8-carboxamide; And (3-endo) -N-[(3S) -1- (6-fluoropyridin-2-yl) piperidin-3-yl] -3-hydroxy-8-azabicyclo [3.2.1] A compound selected from octane-8-carboxamide or a pharmaceutically acceptable salt thereof. 47. A pharmaceutical composition comprising a compound according to any one of claims 1 to 46 and a pharmaceutically acceptable carrier. 47. A method of controlling 11βHSD1 or MR, comprising contacting an 11-β hydroxyl steroid dehydrogenase type 1 (11βHSD1) or a mineralocorticoid receptor (MR) with a compound according to any one of claims 1-46. The method of claim 48, wherein the regulation is inhibition.   A method of treating a disease associated with the expression or activity of 11βHSD1 or MR in a patient, comprising administering to the patient a therapeutically effective amount of a compound according to claim 1. 51. The disease according to claim 50, wherein the disease is obesity, diabetes, glucose intolerance, insulin resistance, hyperglycemia, hypertension, hyperlipidemia, cognitive impairment, depression, dementia, glaucoma, cardiovascular disease, osteoporosis, inflammation, cardiovascular, kidney or inflammatory disease, heart failure, atherosclerosis Arteriosclerosis, arteriosclerosis, coronary artery disease, thrombosis, angina pectoris, peripheral vascular disease, vascular wall injury, stroke, dyslipidemia, hyperlipoproteinemia, diabetic dyslipidemia, mixed dyslipidemia, hypercholesterolemia, hypertriglyceridemia Hypertension, metabolic syndrome or general aldosterone-related target organ damage. 47. Use of a compound according to any one of claims 1 to 46 for treating a disease associated with the expression or activity of 11βHSD1 or MR in a patient. 53. The disease according to claim 52, wherein the disease is obesity, diabetes, glucose intolerance, insulin resistance, hyperglycemia, hypertension, hyperlipidemia, cognitive impairment, depression, dementia, glaucoma, cardiovascular disease, osteoporosis, inflammation, cardiovascular, kidney or inflammatory disease, heart failure , Atherosclerosis, arteriosclerosis, coronary artery disease, thrombosis, angina pectoris, peripheral vascular disease, vascular wall damage, stroke, dyslipidemia, hyperlipoproteinemia, diabetic dyslipidemia, mixed dyslipidemia, hypercholesterolemia, hypercholesterolemia Use is triglycerides, metabolic syndrome or general aldosterone-related target organ damage. 47. Use of a compound according to any one of claims 1 to 46 for the manufacture of a medicament for the treatment of a disease associated with the expression or activity of 11βHSD1 or MR in a patient. 55. The disease according to claim 54, wherein the disease is obesity, diabetes, glucose intolerance, insulin resistance, hyperglycemia, hypertension, hyperlipidemia, cognitive impairment, depression, dementia, glaucoma, cardiovascular disease, osteoporosis, inflammation, cardiovascular, kidney or inflammatory disease, heart failure, atherosclerosis Arteriosclerosis, arteriosclerosis, coronary artery disease, thrombosis, angina pectoris, peripheral vascular disease, vascular wall injury, stroke, dyslipidemia, hyperlipoproteinemia, diabetic dyslipidemia, mixed dyslipidemia, hypercholesterolemia, hypertriglyceridemia Use which is hypertension, metabolic syndrome or general aldosterone-related target organ damage.